Indole derivatives useful as glucagon receptor antagonists

ABSTRACT

The present invention is directed to indole derivatives, pharmaceutical compositions containing them and their use in the treatment and/or prevention of disorders and conditions ameliorated by antagonizing one or more glucagon receptors, including for example metabolic diseases such as Type II diabetes mellitus and obesity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application claims priority to United States Provisional PatentApplication No. 62/383,619, filed Sep. 6, 2016, which is herebyincorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to indole derivatives, pharmaceuticalcompositions containing them and their use in the treatment and/orprevention of disorders and conditions ameliorated by antagonizing oneor more glucagon receptors, including for example metabolic diseasessuch as Type II diabetes mellitus and obesity.

BACKGROUND OF THE INVENTION

The World Health Organization (WHO) reports a worldwide prevalence of177 million patients with diabetes, a number that is likely to more thandouble by the year 2030. TYPE II diabetes accounts for approximately 90%of all diabetes cases (World Health Organization,http://www.who.int/diabetes/global-report/en/, updated 2016). Long-termcomplications of TYPE II diabetes include atherosclerosis, heartdisease, stroke, end-stage renal disease, retinopathy leading toblindness, nerve damage, sexual dysfunction, frequent infections andrecalcitrant foot ulcers that can result in lower limb amputation.Diabetics are twice as likely to develop cardiovascular disease or havea stroke, 2 to 6 times more likely to have transient ischemic attacks,and 15 to 40 times more likely to require lower-limb amputation comparedwith the general population. In 2007, the total economic cost ofdiabetes was estimated to be US $174 billion accounting for 1 of every 8health care dollars spent in the United States.

Hyperglycemia in patients with TYPE II diabetes mellitus (previouslydesignated non-insulin-dependent diabetes mellitus, or NIDDM) resultsfrom a combination of peripheral insulin resistance and inadequatepancreatic insulin secretion. These abnormalities lead to decreasedglucose disposal and increased endogenous glucose production. Reversalof these abnormalities, either individually or in combination, canprovide an improvement in blood glucose control.

One site that is critically involved in the maintenance of euglycemia isthe liver. Glucose production is maintained by the opposing actions ofinsulin and glucagon on hepatic glucose output. In TYPE II diabetes, thenormal glucagon-insulin ratio is disrupted. Studies investigating therelationship between hepatic glucose production and plasma glucagonconcentrations have suggested that in patients with TYPE II diabetes,increased glucagon action is largely responsible for the hepatic insulinresistance and increased rates of glucose production (REAVEN, G., etal., “Documentation of Hyperglucagonemia Throughout the Day in Nonobeseand Obese Patients with Noninsulin-Dependent Diabetes Mellitus”, J ClinEndocrinol Metab, 1987; pp 106-110, Vol. 64; and SHAH, P. et al., “Lackof Suppression of Glucagon Contributes to Postprandial Hyperglycemia inSubjects with TYPE II Diabetes Mellitus”, J Clin Endocrinol Metab, 2000,pp 4053-4059, Vol. 85). Both elevated fasting glucagon levels andimpaired suppression of glucagon secretion after meals result inhyperglycemia during the postabsorptive and postprandial states. Apositive correlation of plasma glucagon levels and hepatic glucoseoutput and fasting glucose levels has been documented in humans(DEFRONZO, R. A., et al., “Fasting Hyperglycemia inNon-Insulin-Dependent Diabetes Mellitus: Contributions of ExcessiveHepatic Glucose Production and Impaired Tissue Glucose Uptake”Metabolism, 1989, pp 387-395, Vol. 38; and CONSOLI, A., et al.,“Predominant Role of Gluconeogenesis in Increased Hepatic GlucoseProduction in NIDDM”, Diabetes, 1989, pp 550-557, Vol. 38). Therefore,glucagon receptor antagonist provide a promising approach in reducinghepatic glucose output as a mechanism in improving glycemia in TYPE IIdiabetics.

Glucagon is a 29 amino-acid peptide hormonethat is encoded within theproglucagon gene, and is cleaved specifically in pancreatic α-cells bypro-hormone convertase 2 (PC2) (ROUILLE, Y., et al., “Role of theProhormone Convertase PC2 in the processing of Proglucagon to Glucagon”,FEBS Letters, 1997, pp 119-123, Vol. 413). Within the proglucagon genealso sequences for the glucagon-like peptide 1 (GLP1), glucagon likepeptide 2 (GLP2), oxyntomodulin and glicentin are encoded. Glucagon'ssecretion from α-cells is tightly regulated by a number of factors withthe most important being glucose and insulin (QUESADA, I., et al.,“Physiology of the Pancreatic alpha-cell and Glucagon Secretion: Role inGlucose Homeostasis and Diabetes”, Endocrinology, 2008; pp 5-19, Vol.199). In the face of low glucose levels specific ATP-sensitive K⁺channels are activated generating action potentials and stimulatingglucagon secretion (MACDONALD, P. E., et al., “A KATP Channel-DependentPathway within α-Cells Regulates Glucagon Release from Both Rodent andHuman Islets of Langerhans”, PLOS Biology, 2007, pp 1236-1247, Vol. 5).Additional stimuli such as amino acids (TRABELSI, F., et al.,“Arginine-Induced Pancreatic Hormone Secretion During Exercise in Rats”,J. Appl. Physiol., pp 2528-2533, Vol. 81) and exercise (BOTTGER, I., etal., “The Effect of Exercise on Glucagon Secretion”, J. Clin.Endocrinology and Metabolism, 1972, pp 117-125, Vol. 35) are known tostimulate glucagon secretion but the underlying mechanisms are not wellunderstood.

The major physiological role of glucagon is to counteract the action ofinsulin on hepatic glucose output. Glucagon mediates its effects bybinding to and activating the glucagon receptor that was first describedby Rodbell and colleagues (RODBELL M., et al., “The Glucagon-SensitiveAdenyl Cylcase System in Plasma Membranes of Rat Liver. 3. Binging ofGlucagon: Method of Assay and Specificity.”, J. Biol. Chem., 1971, pp1861-1871, Vol. 246). By sequence homology analysis, glucagon receptor(GCGR) is a member of the Class B family of heptahelical guanosinetriphosphate (GTP)-binding protein (G protein) coupled receptors, whichincludes those for the related peptides, glucagon-like peptide-1 (GLP-1)and glucose-dependent insulinotropic polypeptide (MAYO K. E., et al.,“International Union of Pharmacology. XXXV. The Glucagon ReceptorFamily.”, Pharmacological Reviews, 2003, pp 167-194, Vol. 55). Thereceptor is mainly expressed in liver and in kidney with lesser amountsfound in heart, adipose tissue, adrenal glands, pancreas, cerebralcortex and gastrointestinal tract (HANSEN L H, et al., “GlucagonReceptor mRNA Expression in Rat Tissues.” Peptides, 1995, pp 1163-1166,Vol. 16).

The immediate action of glucagon is rapid and transient. Specifically onthe liver one of the main actions of glucagon is to regulateglycogenolysis. The molecular basis for the action of the hormone ismediated through activation of its cognate receptor, signal transductionto Gsα subunits and activation of adenylate cyclase resulting in a riseof intracellular cAMP levels, and subsequent activation of proteinkinase A (PKA). Activation of PKA results in activation of glycogenphopshorylase and inactivation of glycogen synthase resulting in a netincrease in gluconeogenesis via glycogenolysis (JIANG, G., et al.,“Glucagon and Regulation of Glucose Metabolism”, Am. J. Physiol.Endocrinol. Metab., 2003, pp 671-678, Vol. 284). In addition toglycogenolysis glucagon potentiates gluconeogenesis from precursors suchas lactate, alanine, pyruvate and glycerol. The level of regulationappears to be genomic dependent on and in part through cAMP-dependentPKA activation of CREB and transcriptional activation of gluconeogenicgenes including PGC1α and PEPCK (KOO, S-H, et al., “The CREB CoactivatorTORC2 is a Key Regulator of Fasting Glucose Metabolism”, Nature, 2005,pp 1109-1114, Vol. 437).

The role of GCGR in glucose homeostasis has been studied in mice lackingthe receptor. GCGR null mice show slightly reduced plasma glucose andinsulin levels; these mice also have improved glucose tolerance comparedto wild type mice (GELLING, R., et al., “Lower Blood Glucose,Hyperglucagonemia and Pancreatic Alpha Cell Hyperplasia in GlucagonReceptor Knockout Mice”, PNAS, 2003, pp 1438-1443, Vol. 100). Theheterozygote mice have no obvious phenotype. When challenged withstreptozotocin, the GCGR null mice were resistant to hyperglycemia andpancreatic β-cell destruction suggesting that inhibition of glucagonsignaling promotes β-cell survival and function (CONARELLO, S. L., etal., “Glucagon Receptor Knockout Mice are Resistant to Diet-InducedObesity and Streptozotocin-Mediated Beta Cell Loss and Hyperglycemia”,Dioabetologia, 2007, pp 142-150, Vol. 20). The GCGR null mice did notexhibit hypoglycemia for fasting periods less than 24 hours, and alsorecovered normally after an insulin challenge (GELLING, R., et al.,“Lower Blood Glucose, Hyperglucagonemia and Pancreatic Alpha CellHyperplasia in Glucagon Receptor Knockout Mice”, PNAS, 2003, pp1438-1443, Vol. 100). This suggests presence of alternate signalingpathways from counter regulatory hormones that offset hypoglycemia inthe absence of the glucagon receptor. Liver membranes from GCGR nullmice were found to have an increased response to epinephrine-inducedcAMP production. Additionally, null animals had a 2-fold increase offasting corticosterone levels under prolonged fasting (12-14 hours).When fasting was extended post 24 hours, these mice developed severehypoglycemia.

GCGR null mice exhibit α-cell hyperplasia and increased expressionlevels of the proglucagon gene (GELLING, R., et al., “Lower BloodGlucose, Hyperglucagonemia and Pancreatic Alpha Cell Hyperplasia inGlucagon Receptor Knockout Mice”, PNAS, 2003, pp 1438-1443, Vol. 100).The long term safety of chronic blockade of this pathway in humans isnot known but it is worth mentioning that rodents have a higher capacityof islet cell replication than humans (PARNAUD, G., et al.,“Proliferation of Sorted Human and Rat Beta Cells”, Diabetologia, 2008,pp 91-100, Vol. 51). Specifically rat β-cells can proliferate whenplated on extracellular matrix and this proliferation is furtherenhanced in the presence of exogenous factors such as liraglutide. Incontrast, human β-cells fail to proliferate in vitro. The consequence ofα-cell hyperplasia in the null mouse is an increased processing ofproglucagon and generation of GLP-1 derived from the pancreas. It iswell established that intestinally processed forms of GLP-1 act toinhibit glucagon secretion, increase insulin secretion as well as toimprove β-cell glucose sensitivity and β-cell mass. GLP-1 also inhibitsfood intake via the central nervous system (CNS). Therefore, theelevated pancreatic-derived GLP-1 levels in GCGR null mice may accountfor the enhancement of glucose-stimulated insulin secretion and glucosetolerance (SLOOP, K. W., et al., “Hepatic and Glucagon-LikePeptide-1-Mediated Reversal of Diabetes by Glucagon Receptor AntisenseOligonucleotide Inhibitors”, J Clin Invest, 2004, pp 1571-1581, Vol.113). This has been recently validated in an investigation by Gu et al.,in which the authors evaluated a mouse GCGR neutralizing antibody inGLP-1 KO mice and found that the antibody provided no improvement inglucose tolerance during an ipGTT. Based on these results, pancreaticGLP-1 would be a significant contributor to the efficacy of glucagonreceptor antagonists in rodents (GU, W., et al., “Glucagon ReceptorAntagonist-Mediated Improvements in Glycemic Control are Dependent onFunctional Pancreatic GLP-1 Receptor”, Am. J. Physiol. Endocrinol.Metab., 2010, pp E624-E632, Vol. 299).

More recent studies have focused on the function of glucagon receptor onhepatic fatty acid oxidation, lipogenesis and hepatocyte survival.Administration of glucagon promotes a hypolipidemic effect in rats(GUETTE, C., et al., “Effect of Chronic Glucagon Administration onLipoprotein Composition in Normally Fed, Fasted and Cholesterol-FedRats”, Lipids, 1991, pp 451-458, Vol. 26) and resolves steatosis inlactating dairy cows (HIPPEN, A. R., et al., “Alleviation of Fatty Liverin Dairy Cows with 14-Day Intravenous Infusions of Glucagon”, J. DairySci., 1999, pp 1139-1152, Vol. 82). In fact, glucagon has been proposedas a treatment of hepatic steatosis (HIPPEN, A. R., “Glucagon as aPotential Therapy for Ketosis and Fatty Liver”, Vet. Clin. North Am.Food Anim. Pract., 2000, pp 267-282, Vol. 16). Fasting GCGR null micefor 16 hours produces a phenotype with defects in triglyceride clearanceand lipid synthesis. Hepatocytes isolated from these animals havereduced capacity for fatty acid beta-oxidation (LONGUET, C., et al.,“The Glucagon Receptor is Required for the Adaptive Metabolic Responseto Fasting”, Cell Metabolism, 2008, pp 359-371, Vol. 8). In someinstances but not all (CONARELLO, S. L., et al., “Glucagon ReceptorKnockout Mice are Resistant to Diet-Induced Obesity andStreptozotocin-Mediated Beta Cell Loss and Hyperglycemia”, Diabetologia,2007, pp 142-150, Vol. 20), steatosis has been observed in the GCGRknockout animals (LONGUET, C., et al., “The Glucagon Receptor isRequired for the Adaptive Metabolic Response to Fasting”, CellMetabolism, 2008, pp 359-371, Vol. 8) and in pre-clinical models thathave been pharmacologically treated with ASO's (LIANG, Y., et al.,“Reduction in Glucagon Receptor Expression by an AntisenseOligonucleotide Ameliorates Diabetic Syndrome in db/db Mice”, Diabetes,2004, pp 410-417, Vol. 53). The mechanism is PKA independent suggestingalternate glucagon signaling pathways in the liver. The exact mechanismby which glucagon signaling in the liver increases fatty acid oxidationis unclear but part of it appears to be mediated by activation of PPARαvia the mitogen activated protein kinase pathway. Glucagon can activateboth p38 and ERK1/2 in hepatocytes with the former increasing (BARGER,P. M., et al., “Deactivation of Peroxisome Proliferator-ActivatedReceptor-α During Cardiac Hypertrophic Growth”, The J. of ClinicalInvestigation, 2000, pp 1723-1730, Vol. 105) and the latter decreasingPPARα activity (BARGER, P. M., “p38 Mitogen-Activated Protein KinaseActivates Peroxisome Proliferator-activated Receptor α”, J. Biol. Chem.,2001, pp 44495-444501, Vol. 276). The p38 pathway also modulates hepaticlipogenesis with glucagon being inhibitory and insulin stimulatory(XIONG, Y., et al., “p38 Mitogen-activated Protein Kinase Plays anInhibitory Role in Hepatic Lipogenesis”, J. Biol. Chem., 2007, pp4975-4982, Vol. 282). These observations are suggestive that glucagonsignaling is required for the regulation of fatty acid oxidation andsynthesis in the liver. The fact that this mechanism is dissociated fromthe classical glucagon G-protein PKA signal transduction indicates apotential in developing biased antagonists that can favorably affect onesignaling arm vs. others thereby alleviating potential concerns ofsustained inactivation of all glucagon signaling pathways.

A heterozygous missense mutation Gly40Ser that results in a loss offunction has been associated with TYPE II diabetes in a Frenchpopulation (HANSEN, L. H., et al., “The Gly40Ser Mutation in the HumanGlucagon Receptor Gene Associated with NIDDM Results in a Receptor withReduced Sensitivity to Glucagon”, Diabetes, 1996, pp 725-730, Vol. 45).It is not apparent why this mutation has deleterious effects on glucosecontrol since deletion of GCGR in rodents improves glucose tolerance.Recently a patient with a homozygous mutation, Pro86Ser, was describedin the literature. This patient was presented with a benign pancreatictumor and further examination revealed elevated glucagon levels (˜60,000pg/mL) in the presence of normal fasting glucose and insulin levels (YU,R. et al., “Nesidioblastosis and Hyperplasia of a Cells,Microglucagonoma, and Nonfunctioning Islet Cell Tumor of the Pancreas”,Pancreas, 2008, pp 428-431, Vol. 36). The tumor was resected andhistological examination revealed α-cell hyperplasia. Hyperglucagonemiapersisted postoperatively which was suppressed with somatostatintreatment. The glucagon receptor gene was sequenced in this patientwhere she was identified to be homozygous for the Pro86Ser mutation andfurther characterization of this mutation revealed a 10-fold loss offunctional response (ZHUO, C., et al., “Homozygous P86S Mutation of theHuman Glucagon Receptor Is Associated with Hyperglucagonemia, a CellHyperplasia, and Islet Cell Tumor”, Pancreas, 2009, pp 941-946, Vol.38). The presence of elevated glucagon levels was most likely sufficientto maintain glucagon receptor signaling and euglycemia. Since thehomozygous mutation was inherited from both parents it suggests theheterozygous mutation is benign. Since this is a single case report, theassociation of this mutation to α-cell hyperplasia remains to bedetermined.

Glucagon antagonism may provide therapeutic agents to control Type IIdiabetes mellitus, along with traditional diabetes drugs focused onincreasing insulin secretion or improving insulin sensitivity.Preclinical data indicate that the anti-diabetic effects of the GCGRantagonist may be related to dual mechanisms including, 1) a reductionof hepatic glucose output that is due to attenuation of glucagon actionin the liver, and 2) a secondary increase in active GLP-1, which occursas a result of increased processing of pre-proglucagon in the pancreas.

Thus there remains a need for novel glucagon antagonists for thetreatment of metabolic disorders such as Type II diabetes mellitus andobesity.

SUMMARY OF THE INVENTION

The present invention is directed to indole derivatives, compounds offormula (I)

wherein

R¹ is selected from the group consisting of phenyl, naphthyl, thienyl,benzofuranyl, benzothienyl, indazolyl, quinolinyl, pyrazolyl andpyridyl;

wherein the phenyl, naphthyl, thienyl, benzofuranyl, benzothienyl,indazolyl, quinolinyl, pyrazolyl or pyridyl whether alone or as part ofa substituent group is optionally substituted with one to more(preferably one to two) substituents independently selected from thegroup consisting of halogen, C₁₋₆alkyl, fluorinated C₁₋₄alkyl,C₁₋₄alkoxy and fluorinated C₁₋₄alkoxy,

a is an integer from 0 to 2;

each R² is independently selected from the group consisting of halogen,C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy and fluorinated C₁₋₄alkoxy,

R³ is selected from the group consisting of hydrogen, C₁₋₄alkyl andphenyl;

R⁴ is selected from the group consisting of C₁₋₆alkyl, fluorinatedC₁₋₄alkyl, —(C₁₋₂alkyl)-O—(C₁₋₄alkyl), C₃₋₆cycloalkyl,—(C₁₋₂alkyl)-C₃₋₆cycloalkyl, phenyl and —(C₁₋₂alkyl)-phenyl,

wherein the phenyl, whether alone or as part of a substituent group isoptionally substituted with one or more (preferably one to two)substituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy and fluorinatedC₁₋₄alkoxy,

Z is selected from the group consisting of C and N;

and stereoisomers and pharmaceutically acceptable salts thereof.

The present invention is further directed to processes for thepreparation of the compounds of formula (I). The present invention isfurther directed to a product prepared according to the processdescribed herein.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and the product prepared accordingto the process described herein. An illustration of the invention is apharmaceutical composition made by mixing the product prepared accordingto the process described herein and a pharmaceutically acceptablecarrier. Illustrating the invention is a process for making apharmaceutical composition comprising mixing the product preparedaccording to the process described herein and a pharmaceuticallyacceptable carrier.

Exemplifying the invention are methods of treating a disorderameliorated by antagonizing a glucagon receptor (selected from the groupconsisting of Type I diabetes, Type II diabetes mellitus, obesity andrenal disease (including, but not limited to, renal failure as acomplication of diabetes) comprising administering to a subject in needthereof a therapeutically effective amount of any of the compounds orpharmaceutical compositions described above.

In an embodiment, the present invention is directed to a compound offormula (I) for use as a medicament. In another embodiment, the presentinvention is directed to a compound of formula (I) for use in thetreatment of a disorder ameliorated by antagonizing a glucagon receptor(selected from the group consisting of Type I diabetes, Type II diabetesmellitus, obesity and renal disease (including but not limited to, renalfailure as a complication of diabetes). In another embodiment, thepresent invention is directed to a composition comprising a compound offormula (I) for the treatment of a disorder ameliorated by aantagonizing glucagon receptor (selected from the group consisting ofType I diabetes, Type II diabetes mellitus, obesity and renal disease(including but not limited to, renal failure as a complication ofdiabetes).

Another example of the invention is the use of any of the compoundsdescribed herein in the preparation of a medicament for treating: (a)Type I diabetes, (b) Type II diabetes mellitus (c) obesity, (d) renaldisease, in a subject in need thereof. In another example, the presentinvention is directed to a compound as described herein for use in amethods for treating a disorder selected from the group consisting ofType I diabetes, Type II diabetes mellitus, obesity, renal disease (forexample renal failure as a complication of diabetes), in a subject inneed thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of formula (I)

wherein R¹, a, R², R³, R⁴ and Z are as herein defined. The compounds ofthe present invention are useful in the treatment of conditions anddisorders which are meliorated by antagonizing glucagon receptors,including but not limited to Type I diabetes, Type II diabetes mellitus,obesity and renal disease.

In certain embodiments, the present invention is directed to compoundsof formula (I) wherein the scope (or Markush group of possiblesubstituents) for each variable of the compounds of formula (I) (e.g. a,R¹, R², R³, R⁴) is independently selected from the lists defined in theembodiments which follow hereinafter.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R¹ is selected from the group consisting of phenyl,naphthyl, thienyl, benzofuranyl, benzothienyl, indazolyl, pyrazolyl andpyridyl; wherein the phenyl, naphthyl, thienyl, benzofuranyl,benzothienyl, indazolyl, pyrazolyl or pyridyl whether alone or as partof a substituent group is optionally substituted with one to more(preferably one to two) substituents independently selected from thegroup consisting of halogen, C₁₋₆alkyl, fluorinated C₁₋₄alkyl,C₁₋₄alkoxy and fluorinated C₁₋₄alkoxy.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R¹ is selected from the group consisting of phenyl,naphthyl, thienyl, benzofuranyl, benzothienyl, indazolyl, quinolinyl,pyrazolyl and pyridyl; wherein the phenyl, naphthyl, thienyl,benzofuranyl, benzothienyl, indazolyl, quinolinyl, pyrazolyl or pyridylwhether alone or as part of a substituent group is optionallysubstituted with one to two substituents independently selected from thegroup consisting of halogen, C₁₋₆alkyl, fluorinated C₁₋₂alkyl,C₁₋₄alkoxy and fluorinated C₁₋₂alkoxy.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R¹ is selected from the group consisting of phenyl,naphthyl, thienyl, benzofuranyl, benzothienyl, indazolyl, quinolinyl,pyrazolyl and pyridyl; wherein the phenyl, naphthyl, thienyl,benzofuranyl, benzothienyl, indazolyl, quinolinyl, pyrazolyl or pyridylwhether alone or as part of a substituent group is optionallysubstituted with one to two substituents independently selected from thegroup consisting of halogen, C₁₋₆alkyl, fluorinated C₁₋₂alkyl,C₁₋₂alkoxy and fluorinated C₁₋₂alkoxy.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R¹ is selected from the group consisting of phenyland benzothienyl (preferably benzothien-2-yl); wherein the phenyl orbenzothienyl (preferably benzothien-2-yl) is optionally substituted withone to two substituents independently selected from the group consistingof halogen, C₁₋₄alkyl and fluorinated C₁₋₂alkyl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R¹ is selected from the group consisting of4-t-butylphenyl, 4-trifluoromethyl-phenyl, 2,4-dichloro-phenyl,2-methyl-4-chloro-phenyl, 2-methyl-4-trifluoromethyl-phenyl,2-chloro-4-trifluoromethyl-phenyl, benzothien-2-yl and6-fluoro-benzothien-2-yl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R¹ is selected from the group consisting of4-t-butylphenyl, 4-trifluoromethyl-phenyl, 2,4-dichloro-phenyl,2-methyl-4-trifluoromethyl-phenyl, 2-chloro-4-trifluoromethyl-phenyl,benzothien-2-yl and 6-fluoro-benzothien-2-yl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R¹ is selected from the group consisting of4-t-butylphenyl, 4-trifluoromethyl-phenyl,2-methyl-4-trifluoromethyl-phenyl, 2-chloro-4-trifluoromethyl-phenyl,benzothien-2-yl and 6-fluoro-benzothien-2-yl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R¹ is selected from the group consisting of4-trifluoromethyl-phenyl, 2-methyl-4-trifluoromethyl-phenyl and2-chloro-4-trifluoromethyl-phenyl.

In an embodiment, the present invention is directed to compounds offormula (I) wherein a is an integer from 0 to 2. In another embodiment,the present invention is directed to compounds of formula (I) wherein ais an integer from 0 to 1. In another embodiment, the present inventionis directed to compounds of formula (I) wherein a is 0. In anotherembodiment, the present invention is directed to compounds of formula(I) wherein a is 1. In another embodiment, the present invention isdirected to compounds of formula (I) wherein a is 2.

In another embodiment, the present invention is directed to compounds offormula (I) wherein each R² is independently selected from the groupconsisting of halogen, C₁₋₄alkyl, fluorinated C₁₋₂alkyl, C₁₋₄alkoxy andfluorinated C₁₋₂alkoxy. In another embodiment, the present invention isdirected to compounds of formula (I) wherein each R² is independentlyselected from the group consisting of halogen, C₁₋₂alkyl, fluorinatedC₁₋₂alkyl, C₁₋₂alkoxy and fluorinated C₁₋₂alkoxy.

In another embodiment, the present invention is directed to compounds offormula (I) wherein each R² is independently selected from the groupconsisting of halogen, C₁₋₂alkyl, fluorinated C₁₋₂alkyl and C₁₋₂alkoxy.

In another embodiment, the present invention is directed to compounds offormula (I) wherein each R² is independently selected from the groupconsisting of 4-methyl, 6-chloro, 6-methyl, 6-methoxy,6-trifluoromethyl, 4-methyl and 7-fluoro.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R² is selected from the group consisting of6-chloro, 6-methyl, 6-methoxy and 6-trifluoromethyl. In anotherembodiment, the present invention is directed to compounds of formula(I) wherein R² is selected from the group consisting of 6-chloro,6-methyl and 6-methoxy. In another embodiment, the present invention isdirected to compounds of formula (I) wherein R² is 6-methoxy.

In another embodiment, the present invention is directed to compounds offormula (I) wherein a is an integer from 1 to 2; and wherein the R²group is bound at the 4-, 6- and/or 7-positions of the indole core. Inanother embodiment, the present invention is directed to compounds offormula (I) wherein a is an integer from 1 to 2; and wherein the R²group is bound at the 4- and/or 7-positions of the indole core.

In another embodiment, the present invention is directed to compounds offormula (I) wherein a is 2 and the two R² groups are 4-methyl and7-fluoro.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R³ is selected from the group consisting ofhydrogen, methyl and phenyl. In another embodiment, the presentinvention is directed to compounds of formula (I) wherein R³ is selectedfrom the group consisting of hydrogen and phenyl. In another embodiment,the present invention is directed to compounds of formula (I) wherein R³is hydrogen.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R⁴ is selected from the group consisting ofC₁₋₆alkyl, fluorinated C₁₋₄alkyl, —(C₁₋₂alkyl)-O—(C₁₋₄alkyl),C₃₋₆cycloalkyl, —(C₁₋₂alkyl)-C₃₋₆cycloalkyl, phenyl and—(C₁₋₂alkyl)-phenyl, wherein the phenyl, whether alone or as part of asubstituent group is optionally substituted with one or to twosubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, fluorinated C₁₋₂alkyl, C₁₋₄alkoxy and fluorinatedC₁₋₂alkoxy.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R⁴ is selected from the group consisting ofC₁₋₆alkyl, fluorinated C₁₋₄alkyl, —(C₁₋₂alkyl)-O—(C₁₋₄alkyl),C₃₋₆cycloalkyl, —(C₁₋₂alkyl)-C₃₋₆cycloalkyl, phenyl and—(C₁₋₂alkyl)-phenyl, wherein the phenyl, whether alone or as part of asubstituent group is optionally substituted with one or to twosubstituents independently selected from the group consisting ofhalogen, C₁₋₄alkyl, fluorinated C₁₋₂alkyl, C₁₋₂alkoxy and fluorinatedC₁₋₂alkoxy.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R⁴ is selected from the group consisting ofC₁₋₆alkyl, fluorinated C₁₋₄alkyl, —(C₁₋₂alkyl)-O—(C₁₋₄alkyl),C₃₋₆cycloalkyl, —(C₁₋₂alkyl)-C₃₋₆cycloalkyl, phenyl and—(C₁₋₂alkyl)-phenyl, wherein the phenyl is optionally substituted with asubstituent selected from the group consisting of halogen, C₁₋₂alkyl andfluorinated C₁₋₂alkyl.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R⁴ is selected from the group consisting ofC₁₋₆alkyl, fluorinated C₁₋₄alkyl, —(C₁₋₂alkyl)-O—(C₁₋₄alkyl),C₃₋₆cycloalkyl, —(C₁₋₂alkyl)-C₃₋₆cycloalkyl, —(C₁₋₂alkyl)-phenyl,wherein the phenyl is optionally substituted with a halogen.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R⁴ is selected from the group consisting ofn-propyl, 3,3,3-trifluoro-n-propyl, isobutyl, 2-fluoro-isobutyl,4,4,4-trifluoro-n-butyl, 3,3,4,4,4-pentafluoro-n-butyl, n-pentyl,isopentyl, n-hexyl, methoxy-ethyl-, cyclopropyl-methyl-,cyclobutyl-ethyl-, cyclopentyl-ethyl-, cyclohexyl, cyclohexyl-methyl-,cyclohexyl-ethyl-, phenylethyl- and 4-chlorophenyl-ethyl-.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R⁴ is selected from the group consisting ofn-propyl, isobutyl, n-pentyl, n-hexyl, cyclobutyl-ethyl-,cyclopentyl-ethyl-, cyclohexyl, cyclohexyl-methyl- andcyclohexyl-ethyl-.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R⁴ is selected from the group consisting ofisobutyl, n-hexyl, cyclobutyl-ethyl-, cyclohexyl and cyclohexyl-ethyl-.

In another embodiment, the present invention is directed to compounds offormula (I) wherein R⁴ is selected from the group consisting of isobutyland cyclohexyl. In another embodiment, the present invention is directedto compounds of formula (I) wherein R⁴ is isobutyl.

In an embodiment, the present invention is directed to compounds offormula (I) wherein Z is selected from the group consisting of C and N.In another embodiment, the present invention is directed to compounds offormula (I) wherein Z is N. In another embodiment, the present inventionis directed to compounds of formula (I) wherein Z is C.

In another embodiment, the present invention is directed to any one ormore compounds of formula (I) selected from the group consisting of3-[[5-[3-methyl-1-[5-[4-(trifluoromethyl)phenyl]indol-1-yl]butyl]pyridine-2-carbonyl]amino]propanoicacid;3-[[4-[3-methyl-1-[5-[4-(trifluoromethyl)phenyl]indol-1-yl]butyl]benzoyl]amino]propanoicacid;3-[[4-[3-methyl-1-[5-[2-methyl-4-(trifluoromethyl)phenyl]indol-1-yl]butyl]benzoyl]amino]propanoicacid;3-[[4-[1-[5-[2-chloro-4-(trifluoromethyl)phenyl]-6-methoxy-indol-1-yl]-3-methyl-butyl]benzoyl]amino]propanoicacid;3-[[4-[(1S)-1-[5-[2-chloro-4-(trifluoromethyl)phenyl]indol-1-yl]-3-methyl-butyl]benzoyl]amino]propanoicacid; and stereoisomers and pharmaceutically acceptable salts thereof.

In another embodiment, the present invention is directed to any one ormore compounds of formula (I) as described herein, wherein thestereocenter denoted with the “*” symbol is present in a racemicmixture. In another embodiment, the present invention is directed to anyone or more compounds of formula (I) as described herein, wherein thestereocenter denoted with the “*” symbol is present in anS-configuration. In another embodiment, the present invention isdirected to any one or more compounds of formula (I) as describedherein, wherein the stereocenter denoted with the “*” symbol is presentin an R-configuration.

Additional embodiments of the present invention, include those whereinthe substituents selected for one or more of the variables definedherein (i.e. R¹, a, R², R³, R⁴, Z, etc.) are independently selected tobe any individual substituent or any subset of substituents selectedfrom the complete list as defined herein.

In another embodiment of the present invention is any single compound orsubset of compounds selected from the representative compounds listed inTable 1, below.

Representative indole derivatives, compounds of formula (I) of thepresent invention are as listed in Table 1, below. Unless otherwisenoted, wherein a stereogenic center is present in the listed compound,the compound was prepared as a mixture of stereo-configurations. Where astereogenic center is present and an S* or R* designation is noted, theS* and R* designations indicate that the compound was prepared in anenantiomeric excess of one of the stereo-isomers, although the exactstereo-configuration of the center was not determined. Where astereogenic center is present and an S or R designation is noted, the Sand R designations indicate that the compound was prepared in anenantiomeric excess of one of the stereo-isomers, and further that theexact stereo-configuration of the center was determined to be S or R, asnoted.

TABLE 1 Representative Indole Derivatives, Compounds of Formula (I)

ID No. R¹ (R²)_(a) R³ R⁴ Z  1 4-t-butyl-phenyl a = 0 H isobutyl ═C—  24-t-butyl-phenyl a = 0 H isobutyl ═N—  6 4-trifluoro-methyl- a = 0 Hisobutyl ═N— phenyl  7 4-trifluoro-methyl- a = 0 H isobutyl ═C— phenyl 9 2,4-dichloro-phenyl a = 0 H isobutyl ═N— 10 2-methyl-4-chloro- a = 0H 3,3,3-trifluoro- ═C— phenyl n-propyl 11 4-trifluoro-methyl- a = 0phenyl isobutyl ═C— phenyl 14 2-methyl-4-trifluoro- a = 0 H isobutyl ═C—methyl-phenyl 15 benzothien-2-yl a = 0 H isobutyl ═C— 162-chloro-4-trifluoro- a = 0 H isobutyl ═C— methyl-phenyl 176-fluoro-benzothien- a = 0 H isobutyl ═C— 2-yl 18 2-chloro-4-trifluoro-a = 0 H n-propyl ═C— methyl-phenyl 19 4-trifluoro-methyl- a = 0 Hcyclohexyl ═C— phenyl 21 2-chloro-4-trifluoro- 6-trifluoro- H isobutyl═C— methyl-phenyl methyl 22 4-trifluoro-methyl- 6-trifluoro- H isobutyl═C— phenyl methyl 23 2-methyl-4-trifluoro- 6-trifluoro- H isobutyl ═C—methyl-phenyl methyl 24 2-chloro-4-trifluoro- 6-chloro H isobutyl ═C—methyl-phenyl 25 2-methyl-4-trifluoro- 6-chloro H isobutyl ═C—methyl-phenyl 26 4-trifluoro-methyl- a = 0 H n-hexyl ═C— phenyl 274-trifluoro-methyl- a = 0 H cyclohexyl- ═C— phenyl ethyl- 284-trifluoro-methyl- a = 0 H 4-chloro- ═C— phenyl phenyl-ethyl- 294-trifluoro-methyl- a = 0 H n-propyl ═C— phenyl 30 4-trifluoro-methyl- a= 0 H n-pentyl ═C— phenyl 31 4-trifluoro-methyl- a = 0 H4,4,4-trifluoro- ═C— phenyl n-butyl 32 4-trifluoro-methyl- a = 0 Hisopentyl ═C— phenyl 33 4-trifluoro-methyl- a = 0 H cyclohexyl- ═C—phenyl methyl- 34 4-trifluoro-methyl- a = 0 H cyclopentyl- ═C— phenylethyl- 35 2-chloro-4-trifluoro- 6-methoxy H isobutyl ═C— methyl-phenyl36 4-trifluoro-methyl- a = 0 H cyclobutyl- ═C— phenyl ethyl- 374-trifluoro-methyl- a = 0 H phenyl-ethyl- ═C— phenyl 384-trifluoro-methyl- a = 0 H 3,3,4,4,4- ═C— phenyl penta-fluoro- n-butyl39 4-trifluoro-methyl- a = 0 H cyclopropyl- ═C— phenyl methyl- 402-methyl-4-trifluoro- 6-methoxy H isobutyl ═C— methyl-phenyl 414-trifluoro-methyl- a = 0 H methoxy- ═C— phenyl ethyl- 424-trifluoro-methyl- 4-methyl- H isobutyl ═C— phenyl 7-fluoro 432-methyl-4-chloro- 4-methyl- H isobutyl ═C— phenyl 7-fluoro 442-methyl-4-trifluoro- 4-methyl- H isobutyl ═C— methyl-phenyl 7-fluoro45^(a) 2-chloro-4-trifluoro- a = 0 H isobutyl ═C— methyl-phenyl 462-chloro-4-trifluoro- 4-methyl- H isobutyl ═C— methyl-phenyl 7-fluoro 474-trifluoro-methyl- a = 0 H 2-fluoro- ═C— phenyl isobutyl 482-chloro-4-trifluoro- 6-methyl H isobutyl ═C— methyl-phenyl ^(a)Compound#45 was prepared in an enantiomeric excess of the correspondingS-enantiomer, as described in more detail in Example 33 which followshereinafter.

Definitions

As used herein, “halogen” shall mean chlorine, bromine, fluorine andiodine. Preferably, the halogen is selected from the group consisting ofchlorine, bromine and fluorine.

As used herein, the term “C_(X-Y)alkyl” wherein X and Y are integers,whether used alone or as part of a substituent group, include straightand branched chains containing between X and Y carbon atoms. Forexample, C₁₋₄alkyl radicals include straight and branched chains ofbetween 1 and 4 carbon atoms, including methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl and t-butyl.

One skilled in the art will recognize that the term “—(C_(X-Y)alkyl)-”,wherein X and Y are integers, shall denote any straight or branchedC_(X-Y)alkyl carbon chain as herein defined, wherein said C_(X-Y)alkylchain is divalent and is further bound through two points of attachment,preferably through two terminal carbon atoms. For example, the term“—(C₁₋₂alky)-” shall include —CH₂— and —CH₂CH₂—.

As used herein, unless otherwise noted, the term “fluorinated C₁₋₄alkyl” shall mean any C₁₋₄alkyl group as defined above substituted withat least one fluorine atom. Suitable examples include but are notlimited to —CF₃, —CH₂—CF₃, —CF₂—CF₂—CF₂—CF₃, and the like.

As used herein, unless otherwise noted, “C₁₋₄alkoxy” shall denote anoxygen ether radical of the above described straight or branched chainalkyl groups containing one to four carbon atoms. For example, methoxy,ethoxy, n-propoxy, isopropoxy, sec-butoxy, t-butoxy, and the like.

As used herein, unless otherwise noted, the term “fluorinatedC₁₋₄alkoxy” shall mean any C₁₋₄alkoxy group as defined above substitutedwith at least one fluoro atom. Suitable examples include but are notlimited to —OCF₃, —OCH₂—CF₃, —OCF₂—CF₂—CF₂—CF₃, and the like.

As used herein, unless otherwise noted, the term “C_(X-Y)cycloalkyl”,wherein X and Y are integers, shall mean any stable X- to Y-memberedmonocyclic, saturated ring system. For example, the term“C₃₋₆cycloalkyl” shall include cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

When a particular group is “substituted” (e.g., alkyl, cycloalkyl,phenyl, etc.), that group may have one or more substituents, preferablyfrom one to five substituents, more preferably from one to threesubstituents, most preferably from one to two substituents,independently selected from the list of substituents.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

As used herein, the notation “*” shall denote the presence of astereogenic center.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Preferably, wherein the compound is present as an enantiomer, theenantiomer is present at an enantiomeric excess of greater than or equalto about 80%, more preferably, at an enantiomeric excess of greater thanor equal to about 90%, more preferably still, at an enantiomeric excessof greater than or equal to about 95%, more preferably still, at anenantiomeric excess of greater than or equal to about 98%, mostpreferably, at an enantiomeric excess of greater than or equal to about99%. Similarly, wherein the compound is present as a diastereomer, thediastereomer is present at an diastereomeric excess of greater than orequal to about 80%, more preferably, at an diastereomeric excess ofgreater than or equal to about 90%, more preferably still, at andiastereomeric excess of greater than or equal to about 95%, morepreferably still, at an diastereomeric excess of greater than or equalto about 98%, most preferably, at an diastereomeric excess of greaterthan or equal to about 99%.

Furthermore, some of the crystalline forms for the compounds of thepresent invention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe present invention may form solvates with water (i.e., hydrates) orcommon organic solvents, and such solvates are also intended to beencompassed within the scope of this invention.

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows:

-   AcOH or HOAc=Acetic acid-   AIBN=Azobisisobutyronitrile-   aq.=Aqueous-   BCA=Bicinchoninic acid-   BF₃.Et₂O=Boron trifluoride diethyl etherate-   BPO=Benzoyl Peroxide-   BSA=Bovine Serum Albumin-   Bu₄NF=Tetra-n-butylammonium fluoride-   cAMP=Cyclic adenosine monophosphate-   conc. or con.=Concentrated-   DCE=1,1-Dichloroethane-   DCM=Dichloromethane-   DIPEA or DIEA=Diisopropylethylamine-   DME=Dimethoxyethane-   DMEM=Dulbecco's modified Eagle's medium-   DMF=N,N-Dimethylformamide-   DMSO=Dimethylsulfoxide-   EA=Ethyl acetate-   EDC or EDCl=1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide-   Et=Ethyl-   Et₃N or TEA=Triethylamine-   Et₂O=Diethyl ether-   EtOAc or EA=Ethyl acetate-   FBS=Fetal Bovine Serum-   HATU=O-(7-Azabenzotriazol-1-yl)-N,N,N″,N″-Tetramethyl Uronium    Hexafluorophosphate-   HBSS=Hank's Buffered Saline Solution-   HEPES (buffer)=4-(2-Hydroxyethyl)-1-piperizine ethane sulfonic acid-   HOBt=1-Hydroxybenzotriazole-   HPLC=High Pressure Liquid Chromatography-   K[N(SiMe)₃]₂=Potassium bis(trimethylsilyl)amide-   KOt-Bu=Potassium tert-Butoxide-   LC-MS=Liquid Chromatography-Mass Spectroscopy-   Martin's Reagent or =Dess-Martin Periodinane-   Me=Methyl-   MeOH=Methanol-   Me₃SiCN=Trimethyl silyl cyanide-   Me₃SiI=Trimethylsilyl iodide-   Mesyl or Ms=Methylsulfonyl-   MOM=Methoxymethyl ether-   MS=Mass Spectroscopy-   MsCl=Mesyl chloride-   MsO=mesylate (i.e. —O—SO₂—CH₃)-   NaBH(OAc)₃=Sodium triacetoxyborohydride-   NBS=N-Bromosuccinimide-   NIS=N-Iodosuccinimide-   NMM=N-methylmorpholine-   NMP=N-methyl-2-pyrrolidone-   ¹H NMR=Hydrogen Nuclear Magnetic Resonance-   OTf=Trifluoromethanesulfonate (i.e. —O—SO₂—CF₃)-   PCC=Pyridinium chlorochromate-   PdCl₂(PPh₃)₂=Bis(triphenylphosphine) Palladium (II) dichloride-   Pd(OAc)₂=Palladium(II) acetate-   Pd(dba)₂=Tris(dibenzylideneacetone) dipalladium(0)-   Pd₂(dba)₃=Tris(dibenzylideneacetone) dipallaium (0)-   Pd(dppf)Cl₂=1,1′-Bis(diphenylphosphino) ferrocenepalladium    dichloride-   Pd(PPh₃)₄=tetrakis(triphenylphosphine) palladium (0)-   PE=Petroleum ether-   PEI=Polyethyleneimine-   PPh₃=Tri-phenyl Phosphine-   TEA=Triethylamine-   tert-BuOH=tert-Butanol-   TFA=Trifluoroacetic Acid-   THF=Tetrahydrofuran-   THP=Tetrahydopyran-   TLC=Thin Layer Chromatography-   TMS=Trimethylsilyl-   Tosyl=p-Toluenesulfonyl

As used herein, unless otherwise noted, the term “isolated form” shallmean that the compound is present in a form which is separate from anysolid mixture with another compound(s), solvent system or biologicalenvironment. In an embodiment of the present invention, the compound offormula (I) is present in an isolated form. In an embodiment of thepresent invention, the compound of formula (I) is present in an isolatedform.

As used herein, unless otherwise noted, the term “substantially pureform” shall mean that the mole percent of impurities in the isolatedcompound is less than about 5 mole percent, preferably less than about 2mole percent, more preferably, less than about 0.5 mole percent, mostpreferably, less than about 0.1 mole percent. In an embodiment of thepresent invention, the compound of formula (I) is present as asubstantially pure form.

As used herein, unless otherwise noted, the term “substantially free ofa corresponding salt form(s)” when used to described the compound offormula (I) shall mean that mole percent of the corresponding saltform(s) in the isolated compound of formula (I) is less than about 5mole percent, preferably less than about 2 mole percent, morepreferably, less than about 0.5 mole percent, most preferably less thanabout 0.1 mole percent. In an embodiment of the present invention, thecompound of formula (I) is present in a form which is substantially freeof corresponding salt form(s).

As used herein, unless otherwise noted the term “condition, disease ordisorder ameliorated by antagonizing a glucagon receptor” shall mean andcondition, disease or disorders wherein at least one symptom of saidcondition, disease or disorder is alleviated or eliminated when one ormore glucagon receptors are antagonized. Suitable examples include, butare not limited to Type I diabetes, Type II diabetes mellitus, obesityand renal disease, for example renal failure as a complication ofdiabetes. Preferably, the condition, disease or disorder ameliorated byantagonizing a glucagon receptor is selected from the group consistingof Type II diabetes mellitus and obesity.

As used herein, unless otherwise noted, the term “renal disease” shallinclude renal disease relating to renal hypertrophy, glomerular injuryand microalbuminuria in glucose intolerant individuals characterized bypersistent hyperglucagonemia.

As used herein, unless otherwise noted, the terms “treating”,“treatment” and the like, shall include the management and care of asubject or patient (preferably mammal, more preferably human) for thepurpose of combating a disease, condition, or disorder and includes theadministration of a compound of the present invention to prevent theonset of the symptoms or complications, alleviate the symptoms orcomplications, or eliminate the disease, condition, or disorder.

As used herein, unless otherwise noted, the term “prevention” shallinclude (a) reduction in the frequency of one or more symptoms; (b)reduction in the severity of one or more symptoms; (c) the delay oravoidance of the development of additional symptoms; and/or (d) delay oravoidance of the development of the disorder or condition.

One skilled in the art will recognize that wherein the present inventionis directed to methods of prevention, a subject in need of thereof (i.e.a subject in need of prevention) shall include any subject or patient(preferably a mammal, more preferably a human) who has experienced orexhibited at least one symptom of the disorder, disease or condition tobe prevented. Further, a subject in need thereof may additionally be asubject (preferably a mammal, more preferably a human) who has notexhibited any symptoms of the disorder, disease or condition to beprevented, but who has been deemed by a physician, clinician or othermedical profession to be at risk of developing said disorder, disease orcondition. For example, the subject may be deemed at risk of developinga disorder, disease or condition (and therefore in need of prevention orpreventive treatment) as a consequence of the subject's medical history,including, but not limited to, family history, pre-disposition,co-existing (comorbid) disorders or conditions, genetic testing, and thelike.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment. Preferably, the subject has experiencedand/or exhibited at least one symptom of the disease or disorder to betreated and/or prevented.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

To provide a more concise description, some of the quantitativeexpressions herein are recited as a range from about amount X to aboutamount Y. It is understood that wherein a range is recited, the range isnot limited to the recited upper and lower bounds, but rather includesthe full range from about amount X through about amount Y, or any amountor range therein.

As more extensively provided in this written description, terms such as“reacting” and “reacted” are used herein in reference to a chemicalentity that is any one of: (a) the actually recited form of suchchemical entity, and (b) any of the forms of such chemical entity in themedium in which the compound is being considered when named.

One skilled in the art will recognize that, where not otherwisespecified, the reaction step(s) is performed under suitable conditions,according to known methods, to provide the desired product. One skilledin the art will further recognize that, in the specification and claimsas presented herein, wherein a reagent or reagent class/type (e.g. base,solvent, etc.) is recited in more than one step of a process, theindividual reagents are independently selected for each reaction stepand may be the same of different from each other. For example whereintwo steps of a process recite an organic or inorganic base as a reagent,the organic or inorganic base selected for the first step may be thesame or different than the organic or inorganic base of the second step.Further, one skilled in the art will recognize that wherein a reactionstep of the present invention may be carried out in a variety ofsolvents or solvent systems, said reaction step may also be carried outin a mixture of the suitable solvents or solvent systems. One skilled inthe art will further recognize that wherein two consecutive reaction orprocess steps are run without isolation of the intermediate product(i.e. the product of the first of the two consecutive reaction orprocess steps), then the first and second reaction or process steps maybe run in the same solvent or solvent system; or alternatively may berun in different solvents or solvent systems following solvent exchange,which may be completed according to known methods.

Examples of suitable solvents, bases, reaction temperatures, and otherreaction parameters and components are provided in the detaileddescriptions which follow herein. One skilled in the art will recognizethat the listing of said examples is not intended, and should not beconstrued, as limiting in any way the invention set forth in the claimswhich follow thereafter.

As used herein, unless otherwise noted, the term “leaving group” shallmean a charged or uncharged atom or group which departs during asubstitution or displacement reaction. Suitable examples include, butare not limited to, Br, Cl, I, mesylate, tosylate, triflate, and thelike.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

As used herein, unless otherwise noted, the term “nitrogen protectinggroup” shall mean a group which may be attached to a nitrogen atom toprotect said nitrogen atom from participating in a reaction and whichmay be readily removed following the reaction. Suitable nitrogenprotecting groups include, but are not limited to carbamates—groups ofthe formula —C(O)O—R wherein R is for example methyl, ethyl, t-butyl,benzyl, phenylethyl, CH₂═CH—CH₂—, and the like; amides—groups of theformula —C(O)—R′ wherein R′ is for example methyl, phenyl,trifluoromethyl, and the like; N-sulfonyl derivatives—groups of theformula —SO₂—R″ wherein R″ is for example tolyl, phenyl,trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-,2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogenprotecting groups may be found in texts such as T. W. Greene & P. G. M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

As used herein, unless otherwise noted, the term “oxygen protectinggroup” shall mean a group which may be attached to an oxygen atom toprotect said oxygen atom from participating in a reaction and which maybe readily removed following the reaction. Suitable oxygen protectinggroups include, but are not limited to, acetyl, benzoyl,t-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM, THP, and the like.Other suitable oxygen protecting groups may be found in texts such as T.W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

Additionally, chiral HPLC against a standard may be used to determinepercent enantiomeric excess (% ee). The enantiomeric excess may becalculated as follows

[(Rmoles−Smoles)/(Rmoles+Smoles)]×100%

where Rmoles and Smoles are the R and S mole fractions in the resultingmixture such that Rmoles+Smoles=1. The enantiomeric excess mayalternatively be calculated from the specific rotations of the desiredenantiomer and the prepared mixture as follows:

ee=([α−obs]/[α−max])×100.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts include,but are not limited to, the following: acetate, benzenesulfonate,benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calciumedetate, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate(embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

Representative acids which may be used in the preparation ofpharmaceutically acceptable salts include, but are not limited to, thefollowing: acids including acetic acid, 2,2-dichloroacetic acid,acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaricacid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronicacid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hipuric acid,hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lacticacid, lactobionic acid, maleic acid, (−)-L-malic acid, malonic acid,(±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotincacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid,4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid,sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid,p-toluenesulfonic acid and undecylenic acid.

Representative bases which may be used in the preparation ofpharmaceutically acceptable salts include, but are not limited to, thefollowing: bases including ammonia, L-arginine, benethamine, benzathine,calcium hydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodiumhydroxide, triethanolamine, tromethamine and zinc hydroxide.

General Synthesis Methods

Compounds of formula (I), preferably compound of formula (I) wherein Zis C, may be prepared according to the process outlined in Scheme 1.

Accordingly, a suitably substituted compound of formula (V), wherein LG¹is a suitably selected leaving group such as Br, I, OTf (i.e. —OSO₂CF₃),acetyloxy, Cl, and the like and wherein A¹ is selected from the groupconsisting of C₁₋₄alkyl, preferably methyl or ethyl, a known compound orcompound prepared by known methods, is reacted with a suitably selectedcompound of formula (VI), a known compound or compound prepared by knownmethods; in the presence of a suitably selected coupling catalyst suchas Pd(PPh₃)₄, Pd₂(dba)₃, Pd(OAc)₂; in a suitably selected organicsolvent such as THF, 1,4-dioxane, toluene, and the like; to yield thecorresponding compound of formula (VII).

The compound of formula (VII) is reacted with a suitably selectedbrominating agent such as NBS, Br₂, HBr, and the like; in the presenceof a radical initiator such as benzoyl peroxide, AIBN, and the like; ina suitably selected organic solvent such as carbon tetrachloride, DCM,ClCH₂CH₂Cl, and the like; to yield the corresponding compound of formula(VIII).

The compound of formula (VIII) is reacted with a suitably substitutedcompound of formula (IX), wherein LG² is a suitably selected leavinggroup such as Br, I, OTf, and the like, a known compound or compoundprepared by known methods; in the presence of a suitably selected basesuch NaH, KOt-Bu, KH, K[N(SiMe)₃]₂, and the like; in a suitably selectedorganic solvent such as THF, DMF, tert-BuOH, NMP(N-methyl-2-pyrrolidone), and the like; to yield the correspondingcompound of formula (X).

The compound of formula (X) is hydrolyzed to according to known methods,to convert the A¹-alkyl ester to the corresponding carboxylic acid; toyield the corresponding compound of formula (XI). For example, whereinA¹ is methyl, the compound of formula (X) is reacted with LiOH/THF in analcohol such as methanol. In another example, the compound of formula(X) is reacted with a suitably selected acid or base such as NaOH, TFA,and the like; in a suitably selected solvent or mixture of solvents suchas THF/methanol, DCE, DCM, and the like.

The compound of formula (XI) is reacted with a suitably protectedbeta-alanine, a compound of formula (XII) wherein PG¹ is a suitablyselected protecting group such as C₁₋₄alkyl (preferably methyl orethyl), tert-butyl, and the like, a known compound; in the presence of asuitably selected organic base such as DIPEA, TEA, pyridine, and thelike, preferably DIPEA; in the presence of a suitably selected couplingagent such as HATU, HOBt in combination with EDCl, and the like; toyield the corresponding compound of formula (XIII).

The compound of formula (XIII) is reacted with a suitably substitutedboronic acid, a compound of formula (XIV), a known compound or compoundprepared by known methods, in the presence of a suitably selectedpalladium catalyst such as Pd(dppf)Cl₂, Pd(dba)₂, Pd(OAc)₂, and thelike; in the presence of a suitably selected inorganic base such asK₂CO₃, Na₂CO₃, and the like; in a suitably selected solvent or mixtureof solvents, such as THF/water, 1,4-dioxane/water, ethanol/toluene,DME/water, and the like; to yield the corresponding compound of formula(XV).

The compound of formula (XV) is de-protected according to known methods,to yield the corresponding compound of formula (I). For example, whereinthe PG¹ group is t-butyl, the compound of formula (XV) is de-protectedby reacting with a suitably selected acid such as TFA, (CH₃)₃SiI, HCl,and the like; in a suitably selected organic solvent such as DCM, Et₂O,H₂O, and the like. In another example, wherein PG¹ is C₁₋₄alkyl, thecompound of formula (XV) is de-protected by hydrolysis with a suitablyselected base such as NaOH, LiOH, KOH, and the like; in a suitablyselected organic solvent or mixture of solvents such as MeOH/THF,MeOH/1,4-dioxane, and the like.

Compounds of formula (I) preferably compound of formula (I) wherein Z isN, may be prepared according to the process outlined in Scheme 2.

Accordingly, a suitably substituted compound of formula (VIII), preparedfor example as described in Scheme 1 above, is reacted with a suitablysubstituted compound of formula (XVI), a known compound or compoundprepared by known methods; in the presence of a suitably selected basesuch as NaH, KH, LiOH, K[N(SiMe)₃], and the like; in a suitably selectedorganic solvent such as DMF, THF, tert-BuOH, NMP(N-methyl-2-pyrrolidone), and the like; to yield the correspondingcompound of formula (XVII).

The compound of formula (XVII) is hydrolyzed according to known methods,to convert the A¹-alkyl ester to the corresponding carboxylic acid; toyield the corresponding compound of formula (XVIII). For example,wherein A¹ is methyl, the compound of formula (XVII) is reacted withLiOH/THF in an alcohol such as methanol. In another example, thecompound of formula (XVII) is reacted with a suitably selected acid orbase such as NaOH, TFA, and the like; in a suitably selected solvent ormixture of solvents such as THF/methanol, DCE, DCM, and the like.

The compound of formula (XVIII) is reacted with a suitably protectedbeta-alanine, a compound of formula (XII) wherein PG¹ is a suitablyselected protecting group such as C₁₋₄alkyl (preferably methyl orethyl), tert-butyl, and the like, a known compound; in the presence of asuitably selected organic base such as DIPEA, TEA, pyridine, and thelike, preferably DIPEA; in the presence of a suitably selected couplingagent such as HATU, HOBt in combination with EDCl, and the like; toyield the corresponding compound of formula (XV).

The compound of formula (XV) is de-protected according to known methods,to yield the corresponding compound of formula (I). For example, whereinthe PG¹ group is tert-butyl, the compound of formula (XV) isde-protected by reacting with a suitably selected acid such as TFA, HCl,Me₃SiI, and the like; in a suitably selected organic solvent such asDCM, H₂O, Et₂O, and the like. In another example, wherein PG¹ isC₁₋₄alkyl, the compound of formula (XV) is de-protected by hydrolysiswith a suitably selected base such as NaOH, LiOH, KOH, and the like; ina suitably selected organic solvent or mixture of solvents such asMeOH/THF, MeOH/1,4-dioxane, and the like.

Compounds of formula (I) preferably compound of formula (I) wherein Z isC and wherein the carbon atom to which the R⁴ group is bound is presentin an enantiomeric excess, may be prepared according to the processoutlined in Scheme 3.

Accordingly, a suitably substituted compound of formula (XIX), whereinA² is C₁₋₄alkyl, preferably methyl or ethyl, a known compound orcompound prepared by known methods; is reacted with a suitablysubstituted compound of formula (XX), a known compound or compoundprepared by known methods; optionally in the presence of CuCN and LiCl,in a suitably selected organic solvent such as THF and Et₂O and thelike; to yield the corresponding compound of formula (XXI).

The compound of formula (XXI) is reacted with a suitably selectedoxidant such as PCC, Martin's reagent, MnO₂, and the like; in a suitablyselected organic solvent such as DCM, acetonitrile, and the like; toyield the corresponding compound of formula (XXII).

The compound of formula (XXII) is reacted withchloro((1R,2R,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)((1R,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)borane(also known as (+)-diisopinocampheyl chloroborane), a known compound; ina suitably selected organic solvent such as THF, toluene, Et₂O, and thelike; to yield the corresponding, enantiomerically enriched compound offormula (XXIII).

The compound of formula (XXIII) is reacted with mesyl chloride, a knowncompound; in the presence of a suitably selected organic base such asTEA, DIPEA, pyridine, and the like; in a suitably selected organicsolvent such as DCM, toluene, THF, and the like; to yield thecorresponding compound of formula (XXIV).

The compound of formula (XXIV) is reacted with a suitably substitutedcompound of formula (XVI), a known compound or compound prepared byknown methods, a known compound or compound prepared by known methods;in the presence of a suitably selected base such as NaH, KH, KOt-Bu,K[N(SiMe₃)₂], and the like; in a suitably selected organic solvent suchas DMF, THF, NMP (N-methyl-2-pyrrolidone), and the like; to yield thecorresponding compound of formula (XXV).

The compound of formula (XXV) is hydrolyzed to according to knownmethods, to convert the A²-alkyl ester to the corresponding carboxylicacid; to yield the corresponding compound of formula (XXVI). Forexample, wherein A¹ is methyl, the compound of formula (XXV) is reactedwith LiOH/THF in an alcohol such as methanol. In another example, thecompound of formula (XXV) is reacted with a suitably selected acid orbase such as NaOH, TFA, and the like; in a suitably selected solvent ormixture of solvents such as THF/methanol, DCE, DCM, and the like.

The compound of formula (XXVI) is reacted with a suitably protectedbeta-alanine, a compound of formula (XII) wherein PG¹ is a suitablyselected protecting group such as C₁₋₄alkyl (preferably methyl orethyl), tert-Butyl, and the like, a known compound; in the presence of asuitably selected organic base such as DIPEA, TEA, pyridine, and thelike, preferably DIPEA; in the presence of a suitably selected couplingagent such as HATU, HOBt in combination with EDCl, and the like; toyield the corresponding compound of formula (XXVII).

The compound of formula (XXVII) is de-protected according to knownmethods, to yield the corresponding compound of formula (I-C). Forexample, wherein the PG¹ group is tert-butyl, the compound of formula(XXVII) is de-protected by reacting with a suitably selected acid suchas TFA, HCl, Me₃SiI, and the like; in a suitably selected organicsolvent such as DCM, H₂O, Et₂O, and the like. In another example,wherein PG¹ is C₁₋₄alkyl, the compound of formula (XXVII) isde-protected by hydrolysis with a suitably selected base such as NaOH,LiOH, KOH, and the like; in a suitably selected organic solvent ormixture of solvents such as MeOH/THF, MeOH/1,4-dioxane, and the like.

One skilled in the art will recognize that the reactions on theenantiomerically enriched compound of formula (XXIII) and subsequentcompounds are not expected to result in any significant amount ofracemization. Therefore the process of Scheme 3 results in anenantiomerically enriched compound of formula (I).

Compounds of formula (I) may alternatively be prepared according to theprocess outlined in Scheme 4.

Accordingly, a suitably substituted compound of formula (XXII), whereinA² is C₁₋₄alkyl, preferably methyl or ethyl, a known compound orcompound prepared by known methods, is reacted with a suitablysubstituted compound of formula (XXVIII), wherein LG³ is a suitablyselected leaving group such as Br, I, OTf, and the like, a knowncompound or compound prepared by known methods, in the presence of asuitably selected Lewis acids such as TiCl₄, AlCl₃, Me₃SiCN, and thelike; in the presence of a suitably selected organic base such as TEA,DIPEA, pyridine, and the like; in a suitably selected organic solventsuch as DCM, toluene, THF, and the like; to yield the correspondingcompound of formula (XXIX).

The compound of formula (XXIX) is reacted with a suitably selectedreducing agent such as NaBH₄CN, NaBH₄, LiAlH₄, and the like; or asuitably selected acid such as acetic acid, HCl, and the like; in asuitably selected organic solvent such as DCM, toluene, THF, and thelike; to yield the corresponding compound of formula (XXX).

The compound of formula (XXX) is reacted with a suitably selectediodinating agent such as NIS, I₂, ICl, and the like; in the presence ofa catalytic amount of an acid such as TFA, Ag₂SO₄, and the like; in asuitably selected organic solvent such as acetonitrile, DMSO, AcOH, andthe like; to yield the corresponding compound of formula (XXXI).

The compound of formula (XXXI) is reacted with ethynyltrimethylsilane, aknown compound; in the presence of a suitably selected coupling agentsuch as PdCl₂(PPh₃)₂, Pd(PPh₃)₄, Pd(OAc)₂, and the like; in the presenceof CuI; in the presence of a suitably selected organic base such as TEA,DIPEA, pyridine, and the like; in a suitably selected organic solventsuch as THF, DMF, DCM, and the like; to yield the corresponding compoundof formula (XXXII).

The compound of formula (XXXII) is reacted with a suitably substitutedboronic acid, a compound of formula (XIV), a known compound or compoundprepared by known methods, in the presence of a suitably selectedcoupling agent such as PdCl₂(dppf), Pd(PPh₃)₄, Pd(OAc)₂, and the like;in the presence of a suitably selected base such as Cs₂CO₃, K₂CO₃,K₃PO₄, and the like; in a suitably selected organic solvent such as1,4-dioxane, toluene, THF, and the like; to yield the correspondingcompound of formula (XXXIII).

The compound of formula (XXXIII) is reacted with a suitably selectedinorganic base such as CaCO₃, Cs₂CO₃, Bu₄NF, Et₃N, and the like; in thepresence of CuI; in a suitably selected organic solvent such as DMF,DMSO, acetonitrile, and the like; to yield the corresponding compound offormula (XXXIV).

The compound of formula (XXXIV) is substituted for the compound offormula (XVII) in Scheme 2, and reacted as described therein, to yieldthe corresponding compound of formula (I).

Compounds of formula (I) may alternatively be prepared according to theprocess outlined in Scheme 5.

Accordingly, a suitably substituted compound of formula (XXXV), whereinLG⁴ is a suitably selected leaving group such as Br, I, Cl, and thelike, a known compound or compound prepared by known methods, is reactedwith magnesium, according to known methods, to yield the correspondingcompound of formula (XXXVI), wherein LG⁵ is the corresponding Grignardleaving group, such that when LG⁴ is Br, then LG⁵ is MgBr; wherein LG⁴is I, then LG⁵ is MgI, etc.

The compound of formula (XXXVI) is reacted with a suitably substitutedcompound of formula (XXXVII), a known compound or compound prepared byknown methods; in a suitably selected organic solvent such as THF, Et₂O,toluene, and the like; to yield the corresponding compound of formula(XXXVIII).

The compound of formula (XXXVIII) is reacted with a suitably substitutedcompound of formula (XII), wherein PG¹ is a suitably selected protectinggroup such as C₁₋₄alkyl (preferably methyl or ethyl), tert-butyl, andthe like, a known compound; in the presence of a suitably selectedorganic base such as DIPEA, TEA, pyridine, and the like, preferablyDIPEA; in the presence of a suitably selected coupling agent such asHATU, HOBt in combination with EDCl, and the like; to yield thecorresponding compound of formula (XXXIX).

The compound of formula (XXXIX) is reacted with a suitably selectedbrominating agent such as PBr₃, HBr, CBr₄/PPh₃, and the like; in asuitably selected organic solvent such as DCM, Et₂O, AcOH, and the like;to yield the corresponding compound of formula (XL).

The compound of formula (XL) is reacted with a suitably substitutedcompound of formula (XVI), a known compound or compound prepared byknown methods; in the presence of a suitably selected base such as NaH,KOt-Bu, LiOH, K[N{SiMe₃)₂], and the like; in a suitably selected organicsolvent such as DMF, NMP (N-methyl-2-pyrrolidone), THF, and the like; toyield the corresponding compound of formula (XLI).

The compound of formula (XLI) is de-protected according to knownmethods, to yield the corresponding compound of formula (I). Forexample, wherein the PG¹ group is tert-butyl, the compound of formula(XLI) is de-protected by reacting with a suitably selected acid such asTFA, HCl, Me₃SiI, and the like; in a suitably selected organic solventsuch as DCM, H₂O, Et₂O, and the like. In another example, wherein PG¹ isC₁₋₄alkyl, the compound of formula (XV) is de-protected by hydrolysiswith a suitably selected base such as NaOH, LiOH, KOH, and the like; ina suitably selected organic solvent or mixture of solvents such asMeOH/THF, MeOH/1,4-dioxane, and the like.

Pharmaceutical Compositions

The present invention further comprises pharmaceutical compositionscontaining one or more compounds of formula (I) or formula (II) with apharmaceutically acceptable carrier. Pharmaceutical compositionscontaining one or more of the compounds of the invention describedherein as the active ingredient can be prepared by intimately mixing thecompound or compounds with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques. The carrier may takea wide variety of forms depending upon the desired route ofadministration (e.g., oral, parenteral). Thus for liquid oralpreparations such as suspensions, elixirs and solutions, suitablecarriers and additives include water, glycols, oils, alcohols, flavoringagents, preservatives, stabilizers, coloring agents and the like; forsolid oral preparations, such as powders, capsules and tablets, suitablecarriers and additives include starches, sugars, diluents, granulatingagents, lubricants, binders, disintegrating agents and the like. Solidoral preparations may also be coated with substances such as sugars orbe enteric-coated so as to modulate major site of absorption. Forparenteral administration, the carrier will usually consist of sterilewater and other ingredients may be added to increase solubility orpreservation. Injectable suspensions or solutions may also be preparedutilizing aqueous carriers along with appropriate additives.

To prepare the pharmaceutical compositions of this invention, one ormore compounds of the present invention as the active ingredient isintimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration, e.g., oral or parenteral such asintramuscular. In preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. Thus, for liquid oralpreparations, such as for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules, caplets,gelcaps and tablets, suitable carriers and additives include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. For parenterals, the carrier will usuallycomprise sterile water, through other ingredients, for example, forpurposes such as aiding solubility or for preservation, may be included.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Thepharmaceutical compositions herein will contain, per dosage unit, e.g.,tablet, capsule, powder, injection, teaspoonful and the like, an amountof the active ingredient necessary to deliver an effective dose asdescribed above. The pharmaceutical compositions herein will contain,per unit dosage unit, e.g., tablet, capsule, powder, injection,suppository, teaspoonful and the like, of from about 0.01 mg to about1000 mg or any amount or range therein, and may be given at a dosage offrom about 0.01 mg/kg/day to about 300 mg/kg/day, or any amount or rangetherein, preferably from about 0.1 mg/kg/day to about 50 mg/kg/day, orany amount or range therein, preferably from about 0.05 mg/kg/day toabout 15 mg/kg/day, or any amount or range therein. The dosages,however, may be varied depending upon the requirement of the patients,the severity of the condition being treated and the compound beingemployed. The use of either daily administration or post-periodic dosingmay be employed.

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflations. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from about 0.01 mg to about1,000 mg, or any amount or range therein, of the active ingredient ofthe present invention. The tablets or pills of the novel composition canbe coated or otherwise compounded to provide a dosage form yielding theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of material can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of treating conditions, diseases or disorders described inthe present invention may also be carried out using a pharmaceuticalcomposition comprising any of the compounds as defined herein and apharmaceutically acceptable carrier. The pharmaceutical composition maycontain between about 0.01 mg and about 1000 mg of the compound, or anyamount or range therein; preferably from about 1.0 mg to about 500 mg ofthe compound, or any amount or range therein, and may be constitutedinto any form suitable for the mode of administration selected. Carriersinclude necessary and inert pharmaceutical excipients, including, butnot limited to, binders, suspending agents, lubricants, flavorants,sweeteners, preservatives, dyes, and coatings. Compositions suitable fororal administration include solid forms, such as pills, tablets,caplets, capsules (each including immediate release, timed release andsustained release formulations), granules, and powders, and liquidforms, such as solutions, syrups, elixirs, emulsions, and suspensions.Forms useful for parenteral administration include sterile solutions,emulsions and suspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the resulting mixture. Suitable bindersinclude, without limitation, starch, gelatin, natural sugars such asglucose or beta-lactose, corn sweeteners, natural and synthetic gumssuch as acacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The liquid forms in suitably flavored suspending or dispersing agentssuch as the synthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

To prepare a pharmaceutical composition of the present invention, acompound of formula (I) as the active ingredient is intimately admixedwith a pharmaceutical carrier according to conventional pharmaceuticalcompounding techniques, which carrier may take a wide variety of formsdepending of the form of preparation desired for administration (e.g.oral or parenteral). Suitable pharmaceutically acceptable carriers arewell known in the art. Descriptions of some of these pharmaceuticallyacceptable carriers may be found in The Handbook of PharmaceuticalExcipients, published by the American Pharmaceutical Association and thePharmaceutical Society of Great Britain.

Methods of formulating pharmaceutical compositions have been describedin numerous publications such as Pharmaceutical Dosage Forms: Tablets,Second Edition, Revised and Expanded, Volumes 1-3, edited by Liebermanet al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2,edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems,Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.

Compounds of this invention may be administered in any of the foregoingcompositions and according to dosage regimens established in the artwhenever treatment of conditions, disorders or diseases, which areameliorated by antagonizing a glucagon receptor is required.

The daily dosage of the products may be varied over a wide range fromabout 0.01 mg to about 10,000 mg per adult human per day, or any amountor range therein. For oral administration, the compositions arepreferably provided in the form of tablets containing, 0.01, 0.05, 0.1,0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. An effective amount of the drugis ordinarily supplied at a dosage level of from about 0.01 mg/kg toabout 300 mg/kg of body weight per day, or any amount or range therein.Preferably, the range is from about 0.1 to about 1000.0 mg/kg of bodyweight per day, or any amount or range therein. More preferably, fromabout 0.1 to about 50.0 mg/kg of body weight per day, or any amount orrange therein. More preferably, from about 0.5 to about 25.0 mg/kg ofbody weight per day, or any amount or range therein. More preferably,from about 0.5 to about 15 mg/kg of body weight per day, or any amountor range therein. More preferably, from about 0.75 to about 7.5 mg/kg ofbody weight per day, or any amount or range therein. The compounds maybe administered on a regimen of 1 to 4 times per day.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

One skilled in the art will recognize that, both in vivo and in vitrotrials using suitable, known and generally accepted cell and/or animalmodels are predictive of the ability of a test compound to treat orprevent a given disorder.

One skilled in the art will further recognize that human clinical trialsincluding first-in-human, dose ranging and efficacy trials, in healthypatients and/or those suffering from a given disorder, may be completedaccording to methods well known in the clinical and medical arts.

Synthesis Examples

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

In the Examples which follow, some synthesis products are listed ashaving been isolated as a residue. It will be understood by one ofordinary skill in the art that the term “residue” does not limit thephysical state in which the product was isolated and may include, forexample, a solid, an oil, a foam, a gum, a syrup, and the like.

Compounds prepared according to the Examples which list only compoundname, structure, ¹H NMR peaks and MS, were prepared according to theprocedures and general synthesis schemes as described herein, selectingand substituting suitable reactants, starting materials and conditions,as would be readily understood by those skilled in the art (and as notedin Table 2, below).

Example 1—Compound #63-[[5-[3-Methyl-1-[5-[4-(trifluoromethyl)phenyl]indol-1-yl]butyl]pyridine-2-carbonyl]amino]propanoicacid

Step 1: Preparation of 5-(4-(trifluoromethyl)phenyl)-1H-indole

A 50 ml round bottom flask was charged with 5-bromoindole (550 mg, 2.81mmol), 4-trifluoromethylphenyl boronic acid (746 mg, 3.93 mmol),PdCl₂(dppf) (102.6 mg, 0.14 mmol) and K₂CO₃ (2M, 2.81 ml). To themixture was then added 10 ml of 1,4-dioxane and the mixture degassed,refilled with argon, then stirred at 95° C. for 3 hours. The solvent wasremoved under reduced pressure and the residue purified by flash columnchromatography on silica gel (EtOAc/heptanes: 0>>>15%>>>30%) to yield awhite solid. ¹H NMR (CHLOROFORM-d) δ: 8.25 (br s, 1H), 7.88 (d, J=0.7Hz, 1H), 7.72-7.78 (m, 2H), 7.65-7.70 (m, 2H), 7.43-7.52 (m, 2H),7.27-7.30 (m, 1H), 6.56-6.69 (m, 1H).

Step 2: Preparation of methyl 5-isopentylpicolinate

A 50 ml round bottom flask was charged under argon with methyl5-bromopicolinate (3.00 g, 13.9 mmol), isopentylzinc(II) bromide (33.3ml, 16.7 mmol), Pd(PPh₃)₄ (802.4 mg, 0.69 mmol) and 10 ml of anhydrousTHF. The reaction mixture was kept stirring at 60° C. for 16 h. Theresulting mixture was then cooled to room temperature, quenched withaqueous NaHCO₃, extracted with EtOAc. The combined organic layer waswashed with brine, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated and the residue was filtered through a pad of CELITE,washed with dichloromethane three times. The filtrate was concentratedand the residue was purified by flash column chromatography on silicagel (EtOAc/heptane: 0>>>20%>>>40%) to yield a colorless oil. ¹H NMR(CHLOROFORM-d) δ: 8.57 (s, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.65 (br d,J=8.1 Hz, 1H), 3.95-4.05 (m, 3H), 2.59-2.85 (m, 2H), 1.46-1.73 (m, 3H),0.95 (d, J=6.4 Hz, 6H).

Step 3: Preparation of methyl 5-(1-bromo-3-methylbutyl)picolinate

A mixture of methyl 5-isopentylpicolinate (1.68 g, 8.11 mmol), NBS (1.51g, 8.51 mmol) and BPO (98.2 mg, 0.41 mmol) in 40 ml of CCl₄ was heatedunder reflux for 4 hours under argon. The reaction mixture was cooled toroom temperature and the precipitate was filtered off, washed withdichloromethane. The filtrate was concentrated under reduced pressureand the residue was purified by flash column chromatography on silicagel (EtOAc/heptane: 0>>>20%>>>40%) to yield a colorless oil. ¹H NMR(CHLOROFORM-d) δ: 8.73 (s, 1H), 8.14 (d, J=8.1 Hz, 1H), 7.91 (br d,J=8.1 Hz, 1H), 5.05 (t, J=7.8 Hz, 1H), 4.02 (s, 3H), 2.15-2.33 (m, 1H),1.85-2.02 (m, 1H), 1.65-1.79 (m, 1H), 0.96 (t, J=7.2 Hz, 6H).

Step 4: Preparation of5-(3-methyl-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)butyl)picolinicacid

To a suspension of sodium hydride (91.9 mg, 2.30 mmol) in 2 ml ofanhydrous DMF was added 5-(4-(trifluoromethyl)phenyl)-1H-indole (200 mg,0.77 mmol) in 1 ml of DMF under argon. The resulting mixture was stirredat room temperature for 30 mins, then methyl5-(1-bromo-3-methylbutyl)picolinate (284.8 mg, 1.0 mmol) in 2 ml of DMFwas then added to the above mixture. The reaction mixture was keptstirred at room temperature for 2.5 hours. The resulting mixture wasthen diluted with 1N HCl, extracted with ethyl acetate. The residue wasdissolved in THF/MeOH (5 ml, 2:1 v/v), to the resulting mixture was thenadded 1N NaOH and the mixture was stirred for 16 h. The solvent wasconcentrated and the residue was acidified with 1N HCl, extracted withethyl acetate to yield a residue, which was used for the next stepreaction directly.

Step 5: Preparation of methyl3-(5-(3-methyl-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)butyl)picolinamido)propanoate

A mixture of5-(3-methyl-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)butyl)picolinicacid (85.3 mg, 0.19 mmol), methyl 3-aminopropanoate (23.3 mg, 0.23mmol), EDCl (47 mg, 0.25 mmol), HOBt (28.9 mg, 0.19 mmol) and DIEA (48.7mg, 0.38 mmol) in 2 ml of THF was stirred at room temperature for 16 h.The solvent was removed under reduced pressure and the residue waspurified by flash column chromatography on silica gel (EtOAc/heptane:0>>>20%>>>35%) to yield a white foam. ¹H NMR (CHLOROFORM-d) δ: 8.39 (brd, J=2.0 Hz, 2H), 8.09 (d, J=8.3 Hz, 1H), 7.86 (d, J=1.2 Hz, 1H), 7.69(q, J=8.5 Hz, 4H), 7.60 (dd, J=8.1, 2.2 Hz, 1H), 7.31-7.44 (m, 3H), 6.70(d, J=3.2 Hz, 1H), 5.53-5.77 (m, 1H), 3.67-3.77 (m, 5H), 2.63 (t, J=6.1Hz, 2H), 2.33-2.45 (m, 1H), 2.07 (ddd, J=14.2, 8.5, 5.9 Hz, 1H),1.53-1.60 (m, 1H), 1.02 (d, J=6.6 Hz, 6H).

Step 6: Preparation of3-[[5-[3-methyl-1-[5-[4-(trifluoromethyl)phenyl]indol-1-yl]butyl]pyridine-2-carbonyl]amino]propanoicacid

To a solution of methyl3-(5-(3-methyl-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)butyl)picolinamido)propanoate(60 mg, 0.11 mmol) in THF/MeOH (6 ml, v/v 5:1) was added NaOH (1N, 2 ml)and the mixture was stirred at room temperature for 16 hours. Thesolvent was removed under reduced pressure and the residue was quenchedwith 1N HCl, extracted with ethyl acetate. The organic layer wasconcentrated and the residue was purified by Gilson HPLC to yield thetitle compound as a white foam.

¹H NMR (CHLOROFORM-d) δ: 8.36-8.44 (m, 2H), 8.09 (d, J=8.3 Hz, 1H), 7.86(d, J=1.2 Hz, 1H), 7.68 (q, J=8.6 Hz, 4H), 7.59 (dd, J=8.1, 2.2 Hz, 1H),7.37-7.44 (m, 1H), 7.30-7.37 (m, 2H), 6.69 (d, J=3.2 Hz, 1H), 5.67 (dd,J=9.9, 5.7 Hz, 1H), 3.67-3.78 (m, 2H), 2.68 (br t, J=6.0 Hz, 2H),2.32-2.44 (m, 1H), 2.04-2.07 (m, 1H), 1.57 (dquin, J=13.5, 6.6 Hz, 1H),1.01 (d, J=6.4 Hz, 6H); m/z (MH⁺): 524.3.

Example 2—Compound #23-[[5-[1-[5-(4-tert-Butylphenyl)indol-1-yl]-3-methyl-butyl]pyridine-2-carbonyl]amino]propanoicacid

¹H NMR (CHLOROFORM-d) δ: 10.72 (br s, 1H), 8.31-8.46 (m, 2H), 8.08 (d,J=8.1 Hz, 1H), 7.82 (d, J=1.2 Hz, 1H), 7.51-7.61 (m, 3H), 7.36-7.48 (m,3H), 7.26-7.34 (m, 2H), 6.65 (d, J=3.2 Hz, 1H), 5.64 (dd, J=9.9, 5.7 Hz,1H), 3.71 (q, J=6.0 Hz, 2H), 2.67 (br t, J=5.9 Hz, 2H), 2.35 (ddd,J=14.2, 9.7, 5.1 Hz, 1H), 1.97-2.04 (m, 1H), 1.49-1.65 (m, 1H), 1.36 (s,9H), 0.99 (d, J=6.6 Hz, 6H); m/z (MH⁺): 512.3.

Example 3—Compound #93-[[5-[1-[5-(2,4-Dichlorophenyl)indol-1-yl]-3-methyl-butyl]pyridine-2-carbonyl]amino]propanoicacid

¹H NMR (CHLOROFORM-d) δ: 10.36-10.66 (m, 1H), 8.43-8.54 (m, 1H),8.35-8.42 (m, 1H), 8.05-8.13 (m, 1H), 7.65 (s, 1H), 7.61 (dd, J=8.1, 2.0Hz, 1H), 7.47 (d, J=1.7 Hz, 1H), 7.35 (d, J=3.2 Hz, 1H), 7.25-7.31 (m,3H), 7.18-7.23 (m, 1H), 6.52-6.78 (m, 1H), 5.46-5.84 (m, 1H), 3.72 (q,J=6.1 Hz, 2H), 2.69 (t, J=6.0 Hz, 2H), 2.36 (ddd, J=14.4, 9.6, 5.1 Hz,1H), 1.99-2.05 (m, 1H), 1.58 (dquin, J=13.3, 6.6 Hz, 1H), 1.00 (d, J=6.6Hz, 6H); m/z (MH⁺): 525.2.

Example 4—Compound #163-(4-(1-(5-(2-Chloro-4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzamido)propanoicacid

Step 1: Preparation of methyl 4-isopentylbenzoate

A 50 ml round bottom flask was charged with methyl 4-iodobenzoate (3.00g, 11.4 mmol), isopentylzinc(II) bromide (27.5 ml, 0.5M), Pd(PPh₃)₄(661.5 mg, 0.57 mmol) and 15 ml of anhydrous THF. The reaction mixturewas kept stirring at 60° C. for 16 h. The resulting mixture was cooledto room temperature, quenched with aqueous NaHCO₃, extracted with EtOAc.The combined organic layer was washed with brine, dried over Na₂SO₄ andfiltered. The filtrate was concentrated and the residue was filteredthrough a pad of CELITE, washed with dichloromethane three times. Thefiltrate was concentrated and the residue was purified by flash columnchromatography on silica gel (EtOAc/heptane: 0>>>10%) to yield acolorless oil. ¹H NMR (CHLOROFORM-d) δ: 7.94 (s, 2H), 7.25 (d, J=8.1 Hz,2H), 3.90 (s, 3H), 2.52-2.74 (m, 2H), 1.47-1.65 (m, 3H), 0.94 (d, J=6.4Hz, 6H).

Step 2: Preparation of methyl 4-(1-bromo-3-methylbutyl)benzoate

A mixture of methyl 4-isopentylbenzoate (1.70 g, 8.24 mmol), NBS (1.61g, 9.07 mmol) and BPO (199.6 mg, 0.82 mmol) in 25 ml of CCl₄ was heatedunder reflux for 6 hours. The precipitate was filtered off, washed withdichloromethane. The filtrate was concentrated under reduced pressureand the residue was purified by flash column chromatography on silicagel (EtOAc/heptane: 0>>>10%) to yield a colorless oil. ¹H NMR(CHLOROFORM-d) δ: 8.01 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.3 Hz, 2H),4.90-5.10 (m, 1H), 3.92 (s, 3H), 2.20 (ddd, J=14.4, 8.2, 6.7 Hz, 1H),1.96 (dt, J=14.2, 7.1 Hz, 1H), 1.69 (dquin, J=13.4, 6.7 Hz, 1H),0.90-1.02 (m, 6H).

Step 3: Preparation of methyl4-(1-(5-bromo-1H-indol-1-yl)-3-methylbutyl)benzoate

To a solution of 5-bromoindole (332 mg, 1.68 mmol) in THF (2 ml) wasadded KOt-Bu (1.69 ml, 1M) under argon at room temperature and themixture was stirred for 1 hour. To the resulting mixture was added asolution of methyl 4-(1-bromo-3-methylbutyl)benzoate (370 mg, 1.30 mmol)in THF and the resulting mixture was stirred at room temperature for 30mins, then heated at 55° C. for 16 hours. The reaction mixture wasquenched with aqueous NH₄Cl, extracted with EtOAc. The organic layer waswashed with brine, dried over Na₂SO₄, filtered, and the filtrate wasconcentrated under reduced pressure. The crude residue was purified byflash column chromatography on silica gel (EtOAc/heptane: 0>>>5%>>>10%)to yield a white solid. ¹H NMR (CHLOROFORM-d) δ: 7.94 (d, J=8.3 Hz, 2H),7.75 (d, J=1.7 Hz, 1H), 7.32 (d, J=3.4 Hz, 1H), 7.08-7.24 (m, 4H), 6.54(d, J=3.2 Hz, 1H), 5.55 (dd, J=9.8, 5.9 Hz, 1H), 3.88 (s, 3H), 2.23-2.37(m, 1H), 2.03 (ddd, J=14.1, 8.4, 5.9 Hz, 1H), 1.44-1.55 (m, 1H), 0.97(dd, J=6.6, 2.4 Hz, 6H). m/z (MH⁺): 400.0.

Step 4: Preparation of4-(1-(5-bromo-1H-indol-1-yl)-3-methylbutyl)benzoic acid

To a solution of methyl4-(1-(5-bromo-1H-indol-1-yl)-3-methylbutyl)benzoate (61.9 mg, 0.16 mmol)in THF/MeOH (2 ml, v/v 1:1) was added NaOH (1N, 1 ml) and the mixturewas stirred at room temperature for 16 hours. The solvent was removedunder reduced pressure and the residue was quenched with 1N HCl,extracted with ethyl acetate. The organic layer was concentrated toyield a white solid, which was used for the next step reaction directly.

Step 5: Preparation of tert-butyl3-(4-(1-(5-bromo-1H-indol-1-yl)-3-methylbutyl)benzamido)propanoate

A mixture of 4-(1-(5-bromo-1H-indol-1-yl)-3-methylbutyl)benzoic acid(62.9 mg, 0.16 mmol), tert-butyl 3-aminopropanoate (30.7 mg, 0.21 mmol),EDCl (40.6 mg, 0.21 mmol), HOBt (25 mg, 0.16 mmol) and DIEA (63.1 mg,0.49 mmol) in 2 ml of THF was stirred at room temperature for 16 h. Thesolvent was removed under reduced pressure and the residue was purifiedby flash column chromatography on silica gel (EtOAc/heptane: 0>>>20%) toyield a white foam. ¹H NMR (CHLOROFORM-d) δ: 7.75 (s, 1H), 7.66 (d,J=8.3 Hz, 2H), 7.31 (br d, J=2.9 Hz, 1H), 7.15-7.23 (m, 3H), 7.10-7.14(m, 1H), 6.82 (br s, 1H), 6.53 (d, J=3.4 Hz, 1H), 5.54 (br dd, J=9.9,6.0 Hz, 1H), 3.65 (q, J=5.9 Hz, 2H), 2.49-2.56 (m, 2H), 2.24-2.34 (m,1H), 1.98-2.09 (m, 1H), 1.49-1.55 (m, 1H), 1.44 (s, 9H), 0.95-1.01 (m,6H).

Step 6: Preparation of tert-butyl3-(4-(1-(5-(2-chloro-4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzamido)propanoate

A microwave vial was charged with tert-butyl3-(4-(1-(5-bromo-1H-indol-1-yl)-3-methylbutyl)benzamido)propanoate (20.5mg, 0.04 mmol), 2-chloro-4-trifluoromethylphenylboronic acid (11.6 mg,0.05 mmol) and PdCl₂(dppf) (1.5 mg, 0.002 mmol). To the resultingmixture was added 1 ml of 1,4-dioxane, followed by 0.040 ml of K₂CO₃(2M). The vial was capped and the mixture was degassed, re-filled withargon. The reaction mixture was heated at 130° C. for 65 mins undermicrowave irradiation. The mixture was then concentrated and the residuewas purified by flash column chromatography on silica gel(EtOAc/heptane: 0>>>30%) to yield a white solid.

Step 7: Preparation of3-(4-(1-(5-(2-chloro-4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzamido)propanoicacid

To a solution of tert-butyl3-(4-(1-(5-(2-chloro-4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzamido)propanoate(28.7 mg, 0.047 mmol) in 0.5 ml of DCM was added 1 ml of TFA and themixture was stirred at room temperature for 2 hours. The solvent wasremoved and the residue was purified by Gilson HPLC to yield the titlecompound as a white solid.

¹H NMR (CHLOROFORM-d) δ: 7.67 (d, J=8.3 Hz, 2H), 7.53 (d, J=1.2 Hz, 1H),7.51 (s, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.33-7.39 (m, 2H), 7.29 (d, J=8.6Hz, 1H), 7.24 (s, 1H), 7.07 (dd, J=8.4, 1.6 Hz, 1H), 6.78 (br t, J=5.7Hz, 1H), 6.62 (d, J=2.9 Hz, 1H), 5.62 (dd, J=9.4, 6.0 Hz, 1H), 3.71 (q,J=6.1 Hz, 2H), 2.70 (t, J=5.7 Hz, 2H), 2.28-2.37 (m, 1H), 2.02-2.08 (m,1H), 1.59 (dt, J=13.4, 6.7 Hz, 1H), 1.01 (dd, J=6.6, 1.7 Hz, 6H); m/z(MH⁺): 537.3.

Example 5—Compound #13-[[4-[1-[5-(4-tert-Butylphenyl)indol-1-yl]-3-methyl-butyl]benzoyl]amino]propanoicacid

¹H NMR (CHLOROFORM-d) δ: 7.81 (d, J=1.2 Hz, 1H), 7.58-7.64 (m, 2H), 7.54(d, J=8.3 Hz, 2H), 7.41-7.47 (m, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.34-7.39(m, 1H), 7.26-7.33 (m, 2H), 7.18 (d, J=8.1 Hz, 2H), 6.77 (br t, J=5.6Hz, 1H), 6.62 (d, J=2.9 Hz, 1H), 5.58 (dd, J=9.7, 6.0 Hz, 1H), 3.64 (q,J=5.5 Hz, 2H), 2.63 (br d, J=4.9 Hz, 2H), 2.22-2.37 (m, 1H), 2.02 (br d,J=6.1 Hz, 1H), 1.48-1.62 (m, 1H), 1.35 (s, 9H), 0.98 (d, J=6.6 Hz, 6H);m/z (MH⁺): 511.2.

Example 6—Compound #103-[[4-[1-[5-(4-Chloro-2-methyl-phenyl)indol-1-yl]-4,4,4-trifluoro-butyl]benzoyl]amino]propanoicacid

¹H NMR (CHLOROFORM-d) δ: 7.70 (d, J=8.3 Hz, 2H), 7.52 (d, J=1.0 Hz, 1H),7.23-7.31 (m, 5H), 7.15-7.20 (m, 2H), 7.03-7.11 (m, 1H), 6.82-6.92 (m,1H), 6.43-6.72 (m, 1H), 5.47-5.64 (m, 1H), 3.69 (q, J=6.1 Hz, 2H), 2.67(t, J=5.9 Hz, 2H), 2.60 (ddd, J=23.6, 9.8, 5.7 Hz, 2H), 2.25 (s, 3H),2.07-2.22 (m, 2H); m/z (MH⁺): 543.2.

Example 7—Compound #113-[[4-[3-Methyl-1-[2-phenyl-5-[4-(trifluoromethyl)phenyl]indol-1-yl]butyl]benzoyl]amino]propanoicacid

¹H NMR (CHLOROFORM-d) δ: 8.87-9.17 (m, 1H), 7.83-7.92 (m, 1H), 7.61-7.76(m, 6H), 7.38 (s, 7H), 7.25-7.29 (m, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.91(br t, J=6.0 Hz, 1H), 6.64 (s, 1H), 5.68 (dd, J=10.8, 4.4 Hz, 1H), 3.72(q, J=5.9 Hz, 2H), 2.70 (br t, J=5.6 Hz, 2H), 2.43-2.53 (m, 1H),1.96-2.04 (m, 1H), 0.90-1.01 (m, 1H), 0.62 (dd, J=37.7, 6.6 Hz, 6H); m/z(MH⁺): 599.2.

Example 8—Compound #143-[[4-[3-Methyl-1-[5-[2-methyl-4-(trifluoromethyl)phenyl]indol-1-yl]butyl]benzoyl]amino]propanoicacid

¹H NMR (CHLOROFORM-d) δ: 7.64-7.70 (m, 2H), 7.49-7.55 (m, 2H), 7.44-7.49(m, 1H), 7.34-7.40 (m, 2H), 7.29 (d, J=8.6 Hz, 1H), 7.23-7.25 (m, 1H),7.04-7.10 (m, 1H), 6.75-6.83 (m, 1H), 6.58-6.68 (m, 1H), 5.49-5.71 (m,1H), 3.71 (q, J=6.1 Hz, 2H), 2.70 (t, J=5.7 Hz, 2H), 2.33-2.38 (m, 4H),2.02-2.08 (m, 1H), 1.59 (dt, J=13.4, 6.7 Hz, 1H), 1.01 (dd, J=6.6, 1.7Hz, 6H); m/z (MH⁺): 537.3.

Example 9—Compound #153-[[4-[1-[5-(Benzothiophen-2-yl)indol-1-yl]-3-methyl-butyl]benzoyl]amino]propanoicacid

¹H NMR (CHLOROFORM-d) δ: 7.94-8.00 (m, 1H), 7.70-7.84 (m, 2H), 7.62 (s,2H), 7.46 (s, 2H), 7.28-7.36 (m, 3H), 7.20 (m, 3H), 6.73 (br s, 1H),6.58-6.68 (m, 1H), 5.49-5.65 (m, 1H), 3.67 (br d, J=5.4 Hz, 2H), 2.66(br t, J=5.4 Hz, 2H), 2.32 (ddd, J=14.4, 9.7, 5.3 Hz, 1H), 1.97-2.07 (m,1H), 1.46-1.62 (m, 1H), 0.99 (d, J=6.6 Hz, 6H); m/z (MH⁺): 511.1.

Example 10—Compound #173-[[4-[1-[5-(6-Fluorobenzothiophen-2-yl)indol-1-yl]-3-methyl-butyl]benzoyl]amino]propanoicacid

¹H NMR (METHANOL-d₄) δ: 7.91 (s, 1H), 7.73 (br d, J=8.1 Hz, 3H),7.54-7.60 (m, 2H), 7.48-7.54 (m, 2H), 7.42-7.47 (m, 1H), 7.35 (d, J=8.1Hz, 2H), 7.10 (br t, J=9.0 Hz, 1H), 6.62 (d, J=2.9 Hz, 1H), 5.75 (dd,J=10.0, 5.6 Hz, 1H), 3.58 (t, J=6.8 Hz, 2H), 2.59 (t, J=6.8 Hz, 2H),2.35-2.49 (m, 1H), 2.08 (ddd, J=14.2, 8.3, 5.9 Hz, 1H), 1.45-1.57 (m,1H), 1.00 (dd, J=6.4, 4.2 Hz, 6H); m/z (MH⁺): 529.2.

Example 11—Compound #183-[[4-[1-[5-[2-Chloro-4-(trifluoromethyl)phenyl]indol-1-yl]butyl]benzoyl]amino]propanoicacid

¹H NMR (CHLOROFORM-d) δ: 8.02-8.62 (m, 1H), 7.72 (s, 1H), 7.67 (d, J=1.0Hz, 1H), 7.62 (d, J=8.3 Hz, 2H), 7.50 (s, 1H), 7.41-7.47 (m, 1H), 7.34(d, J=3.4 Hz, 1H), 7.25-7.30 (m, 1H), 7.14-7.23 (m, 3H), 6.91 (s, 1H),6.62 (d, J=3.2 Hz, 1H), 5.47 (dd, J=8.8, 6.6 Hz, 1H), 3.62 (q, J=5.8 Hz,2H), 2.61 (br t, J=5.9 Hz, 2H), 2.30 (br s, 1H), 2.13-2.25 (m, 1H),1.30-1.41 (m, 2H), 0.96 (t, J=7.3 Hz, 3H); m/z (MH⁺): 543.2.

Example 12—Compound #193-[[4-[Cyclohexyl-[5-[4-(trifluoromethyl)phenyl]indol-1-yl]methyl]benzoyl]amino]propanoicacid

¹H NMR (CHLOROFORM-d) δ: 7.81 (s, 1H), 7.67 (q, J=8.4 Hz, 6H), 7.34-7.48(m, 5H), 6.71 (br s, 1H), 6.53-6.66 (m, 1H), 4.87-5.13 (m, 1H),3.57-3.74 (m, 2H), 2.66 (br t, J=5.4 Hz, 2H), 2.30-2.43 (m, 1H), 1.71(br d, J=6.4 Hz, 4H), 1.53 (br d, J=12.2 Hz, 1H), 1.17-1.31 (m, 3H),0.95-1.11 (m, 2H); m/z (MH⁺): 549.2.

Example 13—Compound #213-[[4-[1-[5-[2-Chloro-4-(trifluoromethyl)phenyl]-6-(trifluoromethyl)indol-1-yl]-3-methyl-butyl]benzoyl]amino]propanoicacid

¹H NMR (CHLOROFORM-d) δ: 7.64-7.77 (m, 4H), 7.48-7.57 (m, 2H), 7.36-7.47(m, 2H), 7.21-7.30 (m, 2H), 6.88 (br d, J=2.4 Hz, 1H), 6.58-6.70 (m,1H), 5.94 (br s, 1H), 5.65 (dd, J=9.0, 6.4 Hz, 1H), 3.68 (q, J=5.8 Hz,2H), 2.67 (t, J=5.7 Hz, 2H), 2.25-2.39 (m, 1H), 2.05-2.15 (m, 1H),1.46-1.66 (m, 1H), 0.92-1.08 (m, 6H); m/z (MH⁺): 625.2.

Example 14—Compound #223-[[4-[3-Methyl-1-[6-(trifluoromethyl)-5-[4-(trifluoromethyl)phenyl]indol-1-yl]butyl]benzoyl]amino]propanoicacid

¹H NMR (CHLOROFORM-d) δ: 7.65-7.73 (m, 3H), 7.62 (d, J=8.1 Hz, 2H),7.49-7.54 (m, 2H), 7.46 (br d, J=7.8 Hz, 2H), 7.17-7.28 (m, 2H),6.91-7.00 (m, 1H), 6.68-6.89 (m, 1H), 6.64 (d, J=3.2 Hz, 1H), 5.66 (dd,J=9.5, 6.1 Hz, 1H), 3.68 (br d, J=5.4 Hz, 2H), 2.66 (br d, J=5.1 Hz,2H), 2.33 (ddd, J=14.4, 9.4, 5.4 Hz, 1H), 2.05-2.15 (m, 1H), 1.54(dquin, J=13.4, 6.5 Hz, 1H), 1.01 (d, J=6.6 Hz, 6H); m/z (MH⁺): 591.2.

Example 15—Compound #233-[[4-[3-Methyl-1-[5-[2-methyl-4-(trifluoromethyl)phenyl]-6-(trifluoromethyl)indol-1-yl]butyl]benzoyl]amino]propanoicacid

¹H NMR (CHLOROFORM-d) δ: 7.63-7.74 (m, 3H), 7.47-7.56 (m, 2H), 7.37-7.46(m, 2H), 7.23-7.33 (m, 3H), 6.80 (br d, J=3.2 Hz, 1H), 6.63 (d, J=3.2Hz, 1H), 5.65 (dd, J=9.4, 6.2 Hz, 1H), 3.70 (q, J=5.6 Hz, 2H), 2.69 (t,J=5.6 Hz, 2H), 2.24-2.39 (m, 1H), 2.07 (br d, J=19.1 Hz, 4H), 1.47-1.65(m, 1H), 0.97-1.07 (m, 6H); m/z (MH⁺): 605.2.

Example 16—Compound #403-[[4-[1-[6-Methoxy-5-[2-methyl-4-(trifluoromethyl)phenyl]indol-1-yl]-3-methyl-butyl]benzoyl]amino]propanoicacid

¹H NMR (METHANOL-d₄) δ: 7.74 (br d, J=7.6 Hz, 2H), 7.23-7.49 (m, 8H),6.98 (br s, 1H), 6.51 (d, J=3.0 Hz, 1H), 5.74 (dd, J=10.1, 5.6 Hz, 1H),3.69 (s, 3H), 3.59 (t, J=6.8 Hz, 2H), 2.58-2.65 (m, 2H), 2.38-2.48 (m,1H), 2.02-2.21 (m, 4H), 1.51-1.64 (m, 1H), 1.03 (br t, J=6.1 Hz, 6H);m/z (MH⁺): 567.2.

Example 17—Compound #413-[[4-[3-Methoxy-1-[5-[4-(trifluoromethyl)phenyl]indol-1-yl]propyl]benzoyl]amino]propanoicacid

¹H NMR (300 MHz, CDCl₃+D₂O) δ (ppm) 7.85 (s, 1H), 7.59-7.76 (m, 6H),7.14-7.50 (m, 5H), 6.64-6.91 (m, 1H), 5.79-5.84 (m, 1H), 3.65-3.75 (m,2H), 3.35-3.40 (m, 1H), 3.31 (s, 3H), 3.13-3.25 (m, 1H), 2.65-2.69 (m,2H), 2.55-2.57 (m, 2H); m/z (MH⁺): 525.

Example 18—Compound #473-[[4-[3-Fluoro-3-methyl-1-[5-[4-(trifluoromethyl)phenyl]indol-1-yl]butyl]benzoyl]amino]propanoicacid

¹H NMR (300 MHz, CD₃OD) δ (ppm) 7.61-7.90 (m, 9H), 7.40-7.58 (m, 3H),6.67 (d, J=3.3 Hz, 1H), 5.96-6.01 (m, 1H), 3.61 (t, J=6.9 Hz, 2H),2.89-3.04 (m, 2H), 2.59-2.67 (m, 2H), 1.18-1.38 (m, 6H); m/z (MH⁺): 541.

Example 19—Compound #483-[[4-[1-[5-[2-Chloro-4-(trifluoromethyl)phenyl]-6-methyl-indol-1-yl]-3-methyl-butyl]benzoyl]amino]propanoicacid

¹H NMR (METHANOL-d₄) δ: 7.78 (br d, J=4.5 Hz, 1H), 7.72 (dd, J=8.1, 4.5Hz, 2H), 7.62 (s, 1H), 7.39-7.53 (m, 2H), 7.37 (d, J=8.1 Hz, 1H),7.25-7.34 (m, 3H), 6.53 (d, J=3.0 Hz, 1H), 5.74 (dd, J=10.4, 5.3 Hz,1H), 3.59 (t, J=7.1 Hz, 2H), 2.60 (t, J=6.8 Hz, 2H), 2.36-2.47 (m, 1H),2.00-2.14 (m, 4H), 1.47-1.63 (m, 1H), 0.97-1.04 (m, 6H); m/z (MH⁺):571.2.

Example 20—Compound #293-(4-(1-(5-(4-(Trifluoromethyl)phenyl)-1H-indol-1-yl)butyl)benzamido)propanoicacid

Step 1. Synthesis of 5-(4-(trifluoromethyl)phenyl)-1H-indole

Into a 1000-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed 5-bromo-1H-indole (10000 mg, 51.28mmol, 1.00 equiv). To the mixture was then added4-(trifluoromethyl)phenylboronic acid (12700 mg, 66.84 mmol, 1.50 equiv)at 25° C., then Pd(PPh₃)₄ (4750 mg, 4.11 mmol, 0.08 equiv), Na₂CO₃(13600 mg, 128.30 mmol, 2.50 equiv) and toluene/EtOH (300/300 mL). Theresulting solution was stirred for 2 h at 90° C. in an oil bath. Thereaction progress was monitored by LCMS. The resulting mixture wasconcentrated under vacuum. The resulting solution was extracted with3×200 mL of ethyl acetate and the organic layers combined. The resultingmixture was washed with 3×150 mL of brine. The mixture was dried oversodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column with PE:EA (5:1) to yield5-(4-(trifluoromethyl)phenyl)-1H-indole as a white solid.

Step 2. Synthesis of methyl 4-butylbenzoate

Into a 15-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of 1-bromobutane (3 g,21.90 mmol, 2.00 equiv) in 1,3-dimethyl-tetrahydropyrimidin-2(1H)-one(10 mL), methyl 4-iodobenzoate (2.87 g, 10.95 mmol, 1.00 equiv),NiI₂.6H₂O (0.5 g, 1.19 mmol, 0.11 equiv),4,4′-di-tert-butyl-2,2′-bipyridine (0.15 g, 0.56 mmol, 0.05 equiv),1,2-bis(diphenylphosphino)benzene (0.25 mg, 0.56 mmol, 0.05 equiv),manganese (1.21 g, 22.00 mmol, 2.00 equiv) and pyridine (87 mg, 1.10mmol, 0.10 equiv). The resulting solution was stirred overnight at 85°C. in an oil bath and then diluted with 15 mL of H₂O after it was cooledto room temperature. The resulting mixture was extracted with 3×30 mL ofethyl acetate. The combined organic layers were washed with 2×30 mL ofbrine and dried over anhydrous sodium sulfate. The residue was appliedonto a silica gel column and eluted with ethyl acetate/petroleum ether(1:9) to yield methyl 4-butylbenzoate as a white solid. LC-MS (ES, m/z)193 [M+H]⁺

Step 3. Synthesis of methyl 4-(1-bromobutyl)benzoate

Into a 500-mL round-bottom flask, was placed a solution of methyl4-butylbenzoate (2.5 g, 13.02 mmol, 1.00 equiv) in CCl₄ (50 mL), NBS(2.7 g, 15.17 mmol, 1.20 equiv) and benzoic peroxyanhydride (0.16 g,0.66 mmol, 0.05 equiv). The resulting solution was heated under refluxfor 2 h and then cooled to room temperature. The solids were filtratedout. The filtrate was applied onto a silica gel column and eluted withethyl acetate/petroleum ether (1:4) to yield methyl 4-(1-bromobutyl)benzoate as light yellow oil. LC-MS (ES, m/z) 271 [M+H]+.

Step 4. Synthesis of4-(1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)butyl)benzoic acid

Into a 15-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of sodium hydride (69 mg,1.73 mmol, 1.50 equiv, 60%) in N, N-dimethylformamide (2 mL). To theresulting mixture was then added a solution of 5-(4-(trifluoromethyl)phenyl)-1H-indole (300 mg, 1.15 mmol, 1.00 equiv, 100%) in N,N-dimethylformamide (2 mL) dropwise with stirring at 0° C. The resultingsolution was stirred for 1 h at 0° C. To the resulting mixture was thenadded a solution of methyl 4-(1-bromobutyl)benzoate (374 mg, 1.38 mmol,1.20 equiv, 100%) in N,N-dimethylformamide (2 mL) dropwise with stirringat 0 C. The resulting solution was allowed to react, with stirring,overnight at room temperature and then quenched by the addition of 5 mLof water. The pH of the solution was adjusted to pH2 with 1N HCl. Theresulting solution was extracted with 3×20 mL of ethyl acetate. Theorganic layers were combined, dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with ethyl acetate/petroleum ether (1:4) to yield4-(1-(5-(4-(trifluoromethyl) phenyl)-1H-indol-1-yl) butyl) benzoic acidas light yellow oil. LC-MS (ES, m/z) 438 [M+H]⁺.

Step 5. Synthesis of ethyl3-(4-(1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)butyl)benzamido)propanoate

Into a 50-mL round-bottom flask, was placed a solution of4-(1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)butyl)benzoic acid(213 mg, 0.49 mmol, 1.00 equiv, 100%) in DMF (20 mL), HATU (370 mg, 0.97mmol, 2.00 equiv, 100%), DIEA (252 mg, 1.95 mmol, 4.00 equiv, 100%) andethyl 3-aminopropanoate hydrochloride (89 mg, 0.58 mmol, 1.20 equiv,100%). The resulting solution was stirred overnight at room temperatureand then quenched by the addition of 50 mL of water. The resultingmixture was extracted with 3×30 mL of ethyl acetate. The combinedorganic layers were washed with 2×20 mL of brine, dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column and eluted with ethyl acetate/petroleum ether(1:4) to yield ethyl 3-(4-(1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl) butyl) benzamido)propanoate as light yellow oil.LC-MS (ES, m/z) 538 [M+H]⁺.

Step 6. Synthesis of3-(4-(1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)butyl)benzamido)propanoicacid

Into a 25-mL round-bottom flask, was placed a solution of ethyl3-(4-(1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)butyl)benzamido)propanoate(200 mg, 0.37 mmol, 1.00 equiv, 100%) in tetrahydrofuran (8 mL), asolution of in methanol (2 mL) and a solution of lithium hydroxidehydrate (156 mg, 3.72 mmol, 10.00 equiv, 100%) in water (2 mL). Theresulting solution was stirred for 2 h at room temperature. The pH valueof the solution was adjusted to pH2 with 1N HCl. The resulting mixturewas extracted with 4×20 mL of ethyl acetate. The combined organic layerswere dried over anhydrous sodium sulfate and concentrated under vacuum.The resulting residue (150 mg) was purified by Prep-HPLC with thefollowing conditions (1#-Waters 2767-1): Column, SunFire Prep C18, 5 um,19*150 mm; mobile phase, water in 0.05% TFA and CH₃CN (45% CH₃CN up to80% in 10 min, up to 100% in 2 min, down to 45% in 2 min); Detector, UV254 nm to yield 3-(4-(1-(5-(4-(trifluoromethyl) phenyl)-1H-indol-1-yl)butyl)benzamido)propanoic acid as a white solid.

¹H-NMR (300 MHz, CD₃OD) δ 7.88-7.89 (d, J=0.9 Hz, 1H), 7.69-7.84 (m,6H), 7.59 (d, J=3.0 Hz, 1H), 7.36-7.49 (m, 4H), 6.66 (d, J=3.3 Hz, 1H),5.67-5.52 (m, 1H), 3.61 (d, J=6.9 Hz, 2H), 2.62 (t, J=6.9 Hz, 2H),2.45-2.50 (m, 2H), 2.28-2.44 (m, 2H), 1.35-1.45 (m, 2H), 1.03 (t, J=7.5Hz, 3H); LC-MS (ES, m/z) 509 [M+H]⁺.

Example 21—Compound #273-[[4-[3-Cyclohexyl-1-[5-[4-(trifluoromethyl)phenyl]indol-1-yl]propyl]benzoyl]amino]propanoicacid

¹H NMR (400 MHz, CD3OD) δ 7.89 (s, 1H), 7.81-7.83 (m, 2H), 7.69-7.75 (m,4H), 7.55 (s, 1H), 7.44-7.47 (m, 2H), 7.36 (d, J=8.0 Hz, 2H), 6.66 (s,1H), 5.62 (s, 1H), 3.59-3.63 (m, 2H), 2.62 (t, J=6.8 Hz, 2H), 2.35-2.44(m, 2H), 1.65-1.78 (m, 5H), 1.15-1.29 (m, 6H), 0.89-0.95 (m, 2H); m/z(MH⁺): 577.

Example 22—Compound #313-[[4-[5,5,5-Trifluoro-1-[5-[4-(trifluoromethyl)phenyl]indol-1-yl]pentyl]benzoyl]amino]propanoicacid

¹H NMR (300 MHz, CD₃OD) δ (ppm) 7.90 (d, J=1.2 Hz, 1H), 7.69-7.84 (m,6H), 7.59 (d, J=3.3 Hz, 1H), 7.37-7.51 (m, 4H), 6.68 (d, J=3.3 Hz, 1H),5.71-5.77 (m, 1H), 3.56-3.63 (m, 2H), 2.62 (t, J=6.9 Hz, 2H), 2.19-2.57(m, 4H), 1.58-1.68 (m, 2H); m/z (MH⁺): 577.

Example 23—Compound #333-[[4-[2-Cyclohexyl-1-[5-[4-(trifluoromethyl)phenyl]indol-1-yl]ethyl]benzoyl]amino]propanoicacid

¹H NMR (300 MHz, CD₃OD) δ 7.89 (s, 1H), 7.82 (d, J=8.1 Hz, 2H),7.67-7.76 (m, 4H), 7.59 (d, J=3.3 Hz, 1H), 7.42-7.50 (m, 2H), 7.35 (d,J=8.1 Hz, 2H), 6.66 (d, J=3.0 Hz, 1H), 5.79-5.84 (m, 1H), 3.61 (t, J=6.9Hz, 2H), 2.63 (t, J=6:9 Hz, 2H) 2.36-2.46 (m, 1H), 2.09-2.18 (m, 1H),1.62-1.91 (m, 5H), 1.07-1.20 (m, 6H); m/z (MH⁺): 563.

Example 24—Compound #343-[[4-[3-Cyclopentyl-1-[5-[4-(trifluoromethyl)phenyl]indol-1-yl]propyl]benzoyl]amino]propanoicacid

¹H NMR (300 MHz, CD3OD) δ 7.89 (s, 1H), 7.72-7.80 (m, 4H), 7.69 (d,J=8.4 Hz, 2H), 7.56-7.57 (m, 1H), 7.35-7.47 (m, 4H), 6.65 (d, J=3.3 Hz,1H), 5.61-5.66 (m, 1H), 3.62 (t, J=6.9 Hz, 2H), 2.59-2.64 (m, 2H),2.22-2.50 (m, 2H), 1.78-1.88 (m, 3H), 1.52-1.60 (m, 4H), 1.30-1.32 (m,2H), 1.07-1.11 (m, 2H); m/z (MH⁺): 563.

Example 25—Compound #373-[[4-[3-Phenyl-1-[5-[4-(trifluoromethyl)phenyl]indol-1-yl]propyl]benzoyl]amino]propanoicacid

¹H NMR (400 MHz, CD₃OD) δ (ppm) 7.91 (s, 1H), 7.83-7.91 (m, 2H),7.68-7.80 (m, 4H), 7.62 (s, 1H), 7.42-7.43 (m, 1H), 7.17-7.35 (m, 6H),7.11-7.13 (m, 2H), 6.70 (d, J=3.3 Hz, 1H), 5.58-5.62 (m, 1H), 3.60 (t,J=6.9 Hz, 2H), 2.55-2.80 (m, 6H); m/z (MH⁺): 571.

Example 26—Compound #393-[[4-[2-Cyclopropyl-1-[5-[4-(trifluoromethyl)phenyl]indol-1-yl]ethyl]benzoyl]amino]propanoicacid

¹H NMR (300 MHz, CD₃OD) δ (ppm) 7.89 (s, 1H), 7.68-7.883 (m, 6H), 7.58(d, J=2.7 Hz, 1H), 7.36-7.49 (m, 4H), 6.65 (d, J=3.3 Hz, 1H), 5.74-5.79(m, 1H), 3.61 (t, J=6.9 Hz, 2H), 2.62 (t, J=6.9 Hz, 2H), 2.46-2.55 (m,1H), 2.04-2.13 (m, 1H), 0.63-0.64 (m, 1H), 0.40-0.43 (m, 2H), 0.19-0.22(m, 2H); m/z (MH⁺): 521.

Example 27—Compound #323-(4-(4-Methyl-1-(5-(4-trifluoromethyl)phenyl)-1H-indol-1-yl)pentyl)benzamido)propanoicacid

Step 1. Synthesis of methyl 4-(4-methylpentyl)benzoate

Into a 15-mL sealed tube, was placed a solution of1-bromo-4-methylpentane (5 g, 30.30 mmol, 2.00 equiv) in1,3-dimethylimidazolidin-2-one (20 mL), methyl 4-iodobenzoate (4 g,15.27 mmol, 1.00 equiv), NiI₂.6H₂O (0.68 g, 1.62 mmol, 0.11 equiv), Mn(1.66 g, 30.18 mmol, 2.00 equiv), pyridine (0.12 g, 1.52 mmol, 0.10equiv), 4,4′-di-tert-butyl-2,2′-bipyridine (0.204 g, 0.76 mmol, 0.05equiv) and 1,2-bis(diphenylphosphino)benzene (0.338 g, 0.76 mmol, 0.05equiv). The reaction mixture was stirred overnight at 85° C. in an oilbath and then quenched by the addition of 100 mL of water, then cooledto room temperature. The resulting mixture was extracted with 3×100 mLof ethyl acetate. The combined organic layers were dried over anhydroussodium sulfate and concentrated under vacuum. The residue was appliedonto a silica gel column and eluted with petroleum ether (100%) to yieldof methyl 4-(4-methylpentyl)benzoate as colorless oil.

Step 2. Synthesis of methyl 4-(1-bromo-4-methylpentyl)benzoate

Into a 250-mL round-bottom flask, was placed a solution of methyl4-(4-methylpentyl) benzoate (1.5 g, 6.82 mmol, 1.00 equiv, 100%) in CCl₄(60 mL), NBS (1.334 g, 7.49 mmol, 1.10 equiv, 100%) and benzoicperoxyanhydride (82 mg, 0.34 mmol, 0.05 equiv, 100%). The resultingsolution was stirred at reflux for 2 h in an oil bath and then cooled toroom temperature. The solids were filtered out. The filtrate was appliedonto a silica gel column and eluted with PE to yield methyl4-(1-bromo-4-methylpentyl)benzoate as light yellow oil.

Step 3. Synthesis of4-(4-methyl-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)pentyl)benzoicacid

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of sodium hydride (153.2mg, 6.38 mmol, 5.00 equiv, 100%) in N,N-dimethylformamide (1 mL) andthen a solution of 5-(4-(trifluoromethyl)phenyl)-1H-indole (200 mg, 0.77mmol, 1.00 equiv, 100%) in N,N-dimethylformamide (1 mL) added at 0° C.The resulting mixture was stirred for 1 h at 0° C., and then a solutionof methyl 4-(1-bromo-4-methylpentyl)benzoate (296.9 mg, 1.00 mmol, 1.30equiv, 100%) in N,N-dimethylformamide (1 mL) was added. The resultingsolution was stirred overnight at room temperature and then quenched bythe addition of 20 mL of water. The resulting solution was extractedwith 3×20 mL of ethyl acetate. The combined organic layers were driedover anhydrous sodium sulfate and concentrated under vacuum. The residuewas purified by chromatography over a silica gel column with ethylacetate/petroleum ether (1:2-1:1) to yield4-(4-methyl-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)pentyl)benzoicacid as light yellow oil. LC-MS (ES, m/z) 464 [M−H]⁺.

Step 4. Synthesis of ethyl3-(4-(4-methyl-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)pentyl)benzamido)propanoate

Into a 25-mL round-bottom flask, was placed a solution of4-(4-methyl-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)pentyl)benzoicacid (120 mg, 0.26 mmol, 1.00 equiv, 100%) in N,N-dimethylformamide (4mL), HATU (197.6 mg, 0.52 mmol, 2.00 equiv, 100%), DIEA (134.16 mg, 1.04mmol, 4.00 equiv, 100%) and ethyl 3-aminopropanoate hydrochloride (47.4mg, 0.31 mmol, 1.20 equiv, 100%). The resulting solution was stirredovernight at room temperature and then quenched by the addition of 20 mLof water. The resulting solution was extracted with 3×20 mL of ethylacetate. The organic layers were combined, dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was applied onto asilica gel column and eluted with ethyl acetate/petroleum ether (1:4) toyield ethyl3-(4-(4-methyl-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)pentyl)benzamido)propanoateas yellow oil. LC-MS (ES, m/z) 565 [M+H]⁺.

Step 5. Synthesis of3-(4-(4-methyl-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)pentyl)benzamido)propanoicacid

Into a 100-mL round-bottom flask, was placed a solution of ethyl3-(4-(4-methyl-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)pentyl)benzamido)propanoate(120 mg, 0.21 mmol, 1.00 equiv, 100%) in tetrahydrofuran (4 mL) and asolution of LiOH.H₂O (89 mg, 2.12 mmol, 10.00 equiv, 100%) inmethanol/H₂O (1/1 mL). The resulting solution was stirred for 1 h atroom temperature. The reaction was then quenched by the addition of 10mL of water. The pH value of the solution was adjusted to pH2 with 1NHCl. The resulting solution was extracted with 3×20 mL of ethyl acetate.The combined organic layers were dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by asilica gel column with dichloromethane/methanol (100:0-1:15). Theresulting residue (100 mg) was purified by Prep-HPLC with the followingconditions (1#-Waters 2767-1): Column, SunFire Prep C18, 5 um, 19*150mm; mobile phase: water in 0.05% TFA and CH₃CN (40% CH₃CN up to 85% in10 min, up to 100% in 2 min, down to 40% in 2 min) Detector, UV 254 nmto yield3-(4-(4-methyl-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)pentyl)benzamido)propanoicacid as a white solid.

¹H NMR (300 MHz, CD₃OD) δ 7.89 (s, 1H), 7.81 (d, J=7.5 Hz, 2H),7.68-7.76 (m, 4H), 7.56-7.57 (m, 1H), 7.35-7.44 (m, 4H), 6.65 (d, J=3.3Hz, 1H), 5.61 (d, J=6.0 Hz, 1H), 3.61 (t, J=7.2 Hz, 2H), 2.62 (t, J=7.2Hz, 2H), 2.33-2.43 (m, 2H), 1.64-1.66 (m, 1H), 1.21-1.29 (m, 2H),0.89-0.94 (m, 6H); LC-MS (ES, m/z) 537 [M+H]⁺.

Example 28—Compound #303-[[4-[1-[5-[4-(Trifluoromethyl)phenyl]indol-1-yl]hexyl]benzoyl]amino]propanoicacid

Step 1. Preparation of4-(1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)hexyl)benzoic acid

Into a 15-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of sodium hydride (92 mg,2.30 mmol, 3.00 equiv, 60%) in DMF (2 mL). To the resulting mixture wasthen added a solution of 5-(4-(trifluoromethyl) phenyl)-1H-indole (200mg, 0.77 mmol, 1.00 equiv, 100%) in DMF (2 mL) dropwise with stirring at0° C. The resulting solution was stirred for 1 h at 0° C. before addinga solution of methyl 4-(1-bromohexyl) benzoate (275 mg, 0.92 mmol, 1.20equiv, 100%) in DMF (2 mL) dropwise with stirring at −10° C. Theresulting solution was allowed to react, with stirring, overnight atroom temperature. The reaction was then quenched by the addition of 5 mLof water. The pH value of the solution was adjusted to pH2 with 1N HCl.The resulting solution was extracted with 3×20 mL of ethyl acetate. Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with ethyl acetate/petroleum ether (1:4) to yield4-(1-(5-(4-(trifluoromethyl) phenyl)-1H-indol-1-yl)hexyl)benzoic acid aslight yellow oil. LC-MS (ES, m/z) 466 [M+H]⁺.

Step 2. Preparation of ethyl3-(4-(1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)hexyl)benzamido)propanoate

Into a 50-mL round-bottom flask, was placed a solution of4-(1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)hexyl)benzoic acid(100 mg, 0.21 mmol, 1.00 equiv, 100%) in DMF (10 mL), HATU (163 mg, 0.43mmol, 2.00 equiv, 100%), DIEA (110 mg, 0.85 mmol, 4.00 equiv, 100%) andethyl 3-aminopropanoate hydrochloride (40 mg, 0.26 mmol, 1.20 equiv,100%). The resulting solution was stirred overnight at room temperatureand then the reaction was quenched by the addition of 20 mL of water.The resulting solution was extracted with 3×20 mL of ethyl acetate. Thecombined organic layers were washed with 3×30 mL of brine, dried overanhydrous sodium sulfate and concentrated under vacuum. The residue waspurified by a silica gel column with ethyl acetate/petroleum ether (1:4)to yield ethyl 3-(4-(1-(5-(4-(trifluoromethyl) phenyl)-1H-indol-1-yl)hexyl)benzamido)propanoate as yellow oil. LC-MS (ES, m/z) 565 [M+H]⁺.

Step 3. Preparation of3-(4-(1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)hexyl)benzamido)propanoicacid

Into a 25-mL round-bottom flask, was placed a solution of ethyl3-(4-(5,5,5-trifluoro-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)pentyl)benzamido)propanoate(74 mg, 0.13 mmol, 1.00 equiv, 100%) in tetrahydrofuran (8 mL), asolution of in methanol (2 mL), a solution of lithium hydroxide hydrate(55 mg, 1.31 mmol, 10.00 equiv, 100%) in water (2 mL). The resultingsolution was stirred for 2 h at room temperature. The pH value of thesolution was adjusted to pH2 with 1N HCl. The resulting solution wasextracted with 4×20 mL of ethyl acetate. The combined organic layerswere dried over anhydrous sodium sulfate and concentrated under vacuum.The resulting residue (150 mg) was purified by Prep-HPLC with thefollowing conditions (1#-Waters 2767-1): Column, SunFire Prep C18, 5 um,19*150 mm; mobile phase, water in 0.05% TFA and CH₃CN (45% CH₃CN up to80% in 10 min, up to 100% in 2 min, down to 45% in 2 min); Detector, UV254 nm to yield3-(4-(1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)hexyl)benzamido)propanoicacid as a pink solid.

¹H NMR (CD₃OD, 300 MHz) δ 7.89 (s, 1H), 7.81 (d, J=8.1 Hz, 2H),7.68-7.76 (m, 4H), 7.57 (d, J=2.1 Hz, 1H), 7.35-7.48 (m, 4H), 6.65 (d,J=3.3 Hz, 1H), 5.64-5.69 (m, 1H), 3.61 (t, J=7.2 Hz, 2H), 2.62 (t, J=7.2Hz, 2H), 2.31-2.46 (m, 2H), 1.29-1.38 (m, 6H), 0.88 (t, J=6.9 Hz, 3H);LC-MS (ES, m/z) 535 [M+H]⁺.

Example 29—Compound #263-(4-(1-(5-(4-(Trifluoromethyl)phenyl)-1H-indol-1-yl)heptyl)benzamido)propanoicacid

Step 1. Preparation of methyl 4-heptylbenzoate

Into a 250-mL round-bottom flask, was placed a solution of potassiumtrifluoro(heptyl)borate (2 g, 9.71 mmol, 1.30 equiv) in 1,4-dioxane (50mL), methyl 4-bromobenzoate (1.653 g, 7.69 mmol, 1.00 equiv), a solutionof Cs₂CO₃ (6.28 g, 19.26 mmol, 2.50 equiv) in water (25 mL) andPd(dppf)Cl₂ (616 mg, 0.77 mmol, 0.10 equiv). The resulting solution wasstirred overnight at 105° C. in an oil bath. The resulting solution wasextracted with 3×20 mL of ethyl acetate after cooling. The combinedorganic layers were dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was purified by a silica gel column with ethylacetate/petroleum ether (0:100-1:50) to yield methyl 4-heptylbenzoate ascolorless oil.

Step 2. Preparation of methyl 4-(1-bromoheptyl)benzoate

Into a 100-mL round-bottom flask, was placed a solution of methyl4-heptylbenzoate (1.2 g, 5.13 mmol, 1.00 equiv) in CCl₄ (20 mL), NBS(1.1 g, 6.18 mmol, 1.20 equiv) and benzoyl peroxide (20 mg, 0.08 mmol,0.02 equiv). The resulting solution was heated to reflux for 2 h in anoil bath and then cooled to room temperature. The solids were filteredout. The filtrate was concentrated under vacuum. The residue waspurified by a silica gel column with ethyl acetate/petroleum ether(0:100-1:50) to yield methyl 4-(1-bromoheptyl)benzoate as light yellowoil.

Step 3. Preparation of methyl4-(1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)heptyl)benzoate

Into a 50-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of sodium hydride(36 mg, 1.50 mmol, 1.20 equiv) in N,N-dimethylformamide (1 mL). To theflask was then added a solution of5-(4-(trifluoromethyl)phenyl)-1H-indole (200 mg, 0.77 mmol, 1.00 equiv)in N,N-dimethylformamide (1 mL) at 0° C. The mixture was stirred for 1 hat 0° C. before adding a solution of methyl 4-(1-bromoheptyl)benzoate(310 mg, 0.99 mmol, 1.30 equiv) in N,N-dimethylformamide (1 mL). Theresulting solution was stirred overnight at room temperature and thenthe reaction was quenched by the addition of 20 mL of water. Theresulting mixture was extracted with 3×20 mL of ethyl acetate. Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with ethyl acetate/petroleum ether (1:8) to yieldmethyl 4-(1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)heptyl)benzoateas light yellow oil.

Step 4. Preparation of4-(1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)heptyl)benzoic acid

Into a 100-mL round-bottom flask, was placed a solution of methyl4-(1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)heptyl)benzoate (95mg, 0.19 mmol, 1.00 equiv) in tetrahydrofuran (4 mL) and a solution ofLiOH.H₂O (81 mg, 1.93 mmol, 10.00 equiv) in H₂O/MeOH (1/1 mL). Theresulting solution was stirred for 1 h at room temperature and thendiluted with 15 mL of water. The pH value of the solution was adjustedto pH2 with 2 N HCl. The resulting solution was extracted with 3×15 mLof ethyl acetate. The combined organic layers were dried over anhydroussodium sulfate and concentrated under vacuum to yield4-(1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)heptyl)benzoic acid aslight yellow oil. LC-MS (ES, m/z) 478 [M−H]⁺.

Step 5. Preparation of ethyl3-(4-(1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)heptyl)benzamido)propanoate

Into a 25-mL round-bottom flask, was placed a solution of4-(1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)heptyl)benzoic acid(60 mg, 0.13 mmol, 1.00 equiv) in N,N-dimethylformamide (3 mL), HATU (96mg, 0.25 mmol, 2.00 equiv) and DIEA (66 mg, 0.51 mmol, 4.00 equiv). Tothe resulting mixture was then added ethyl 3-aminopropanoatehydrochloride (23.1 mg, 0.15 mmol, 1.20 equiv). The resulting solutionwas stirred overnight at room temperature. The reaction was thenquenched by the addition of 10 mL of water. The resulting solution wasextracted with 3×20 mL of ethyl acetate. The combined organic layerswere dried over anhydrous sodium sulfate and concentrated under vacuum.The residue was applied onto a silica gel column and eluted with ethylacetate/petroleum ether (1:3) to yield ethyl3-(4-(1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)heptyl)benzamido)propanoateas yellow oil. LC-MS (ES, m/z) 579 [M+H]⁺.

Step 6. Preparation of3-(4-(1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)heptyl)benzamido)propanoicacid

Into a 100-mL round-bottom flask, was placed a solution of ethyl3-(4-(1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)heptyl)benzamido)propanoate(90 mg, 0.16 mmol, 1.00 equiv) in tetrahydrofuran (8 mL) and a solutionof LiOH.H₂O (65 mg, 1.55 mmol, 10.00 equiv) in H₂O/MeOH (2/2 mL). Theresulting solution was stirred for 1 h at room temperature. The pH valueof the solution was adjusted to pH2 with 1 N HCl. The resulting solutionwas extracted with 3×10 mL of ethyl acetate. The combined organic layerswere dried over anhydrous sodium sulfate and concentrated under vacuum.The resulting residue was purified by Prep-HPLC with the followingconditions (1#-Waters 2767-1): Column, SunFire Prep C18, 5 um, 19*150mm; mobile phase: water in 0.05% TFA and CH₃CN (50% CH₃CN up to 75% in10 min, up to 100% in 2 min, down to 50% in 2 min); Detector, UV 254 nmto yield3-(4-(1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)heptyl)benzamido)propanoicacid as a light yellow solid.

¹H NMR (400 MHz, CD₃OD) δ 7.89 (s, 1H), 7.81-7.38 (m, 2H), 7.69-7.76 (m,4H), 7.57 (s, 1H), 7.44-7.47 (m, 2H), 7.36-7.38 (m, 2H), 6.66 (s, 1H),5.61-5.68 (m, 1H), 3.61 (t, J=6.8 Hz, 2H), 2.62 (t, J=7.2 Hz, 2H),2.34-2.44 (m, 2H), 1.41-1.49 (m, 4H), 1.23-1.29 (m, 4H), 0.81-0.89 (m,3H); LC-MS (ES, m/z) 551 [M+H]⁺.

Example 30—Compound #383-(4-(4,4,5,5,5-Pentafluoro-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)pentyl)benzamido)propanoicacid

Step 1. Preparation of 1,1,1,2,2-pentafluoro-5-iodopentane

Into a 250-mL three-round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of PPh₃ (14.75 g,56.30 mmol, 1.00 equiv) in dichloromethane (100 mL), imidazole (3.825 g,56.25 mmol, 1.00 equiv) and iodine (14.25 g, 56.10 mmol, 1.00 equiv) at0° C. After stirring for 5 min, 4,4,5,5,5-pentafluoropentan-1-ol (10 g,56.18 mmol, 1.00 equiv) was added. The resulting solution was stirredfor 2.5 h at room temperature. The solids were filtered out. Thefiltrate was concentrated under vacuum to yield1,1,1,2,2-pentafluoro-5-iodopentane as oil.

Step 2. Preparation of methyl 4-(4,4,5,5,5-pentafluoropentyl)benzoate

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of1,1,1,2,2-pentafluoro-5-iodopentane (13 g, 45.14 mmol, 6.00 equiv) in1,3-dimethyl-tetrahydropyrimidin-2(1H)-one (10 mL), methyl4-iodobenzoate (1.9 g, 7.25 mmol, 1.00 equiv), NiI₂.6H₂O (360 mg, 0.86mmol, 0.11 equiv), 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine(100 mg, 0.37 mmol, 0.05 equiv), 1,2-bis(diphenylphosphino)benzene (170mg, 0.38 mmol, 0.05 equiv), manganese (880 mg, 16.00 mmol, 2.00 equiv)and pyridine (64 mg, 0.81 mmol, 0.10 equiv). The resulting solution wasstirred overnight at 85° C. in an oil bath and then diluted with 25 mLof H₂O after cooling. The resulting solution was extracted with 3×30 mLof ethyl acetate. The combined organic layers were washed with 2×30 mLof brine and dried over anhydrous sodium sulfate. The residue wasapplied onto a silica gel column and eluted with ethyl acetate/petroleumether (1:9) to yield methyl 4-(4,4,5,5,5-pentafluoropentyl)benzoate as awhite solid. LC-MS (ES, m/z) 297 [M+H]⁺.

Step 3. Preparation of methyl4-(1-bromo-4,4,5,5,5-pentafluoropentyl)benzoate

Into a 100-mL round-bottom flask, was placed a solution of methyl4-(4,4,5,5,5-pentafluoropentyl)benzoate (1.4 g, 4.73 mmol, 1.00 equiv)in CCl₄ (20 mL), 1-bromopyrrolidine-2,5-dione (1 g, 5.62 mmol, 1.20equiv) and benzoyl peroxide (120 mg, 0.50 mmol, 0.10 equiv). Theresulting solution was heated to reflux for 2 h in an oil bath and thencooled to room temperature. The solids were filtered out. The residuewas applied onto a silica gel column and eluted with petroleumether/EtOAc (9:1) to yield methyl4-(1-bromo-4,4,5,5,5-pentafluoropentyl)benzoate as off-white oil. LC-MS(ES, m/z) 375 [M+H]⁺.

Step 4. Preparation of4-(4,4,5,5,5-pentafluoro-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)pentyl)benzoicacid

A solution of sodium hydride (138 mg, 5.75 mmol, 3.00 equiv) inN,N-dimethylformamide (1 mL), a solution of5-(4-(trifluoromethyl)phenyl)-1H-indole (300 mg, 1.15 mmol, 1.00 equiv)in N,N-dimethylformamide (1 mL) was added at 0° C. The solution wasstirred for 1 h at 0° C., and a solution of methyl4-(1-bromo-4,4,5,5,5-pentafluoropentyl)benzoate (561 mg, 1.50 mmol, 1.30equiv) in N,N-dimethylformamide (1 mL) was added. The resulting solutionwas stirred overnight at room temperature. The resulting solution wasdiluted with 10 mL of H₂O. The pH value of the solution was adjusted topH3 with 2N HCl. The resulting solution was extracted with 3×30 mL ofethyl acetate. The combined organic layers were washed with 2×30 mL ofsodium chloride, dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by a silica gel columnwith ethyl acetate/petroleum ether (1:2) to yield4-(4,4,5,5,5-pentafluoro-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)pentyl)benzoicacid as yellow oil. LC-MS (ES, m/z) 542 [M+H]⁺

Step 5. Preparation of ethyl3-(4-(4,4,5,5,5-pentafluoro-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)pentyl)benzamido)propanoate

Into a 25-mL round-bottom flask, was placed a solution of4-(4,4,5,5,5-pentafluoro-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)pentyl)benzoicacid (260 mg, 0.48 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL),HATU (365 mg, 0.96 mmol, 2.00 equiv), N,N-diisopropylethylamine (248 mg,1.92 mmol, 4.00 equiv) and ethyl 3-aminopropanoate hydrochloride (88 mg,0.58 mmol, 1.20 equiv). The reaction mixture was stirred for 3 h at roomtemperature and then diluted with 20 mL of H₂O. The resulting solutionwas extracted with 3×30 mL of ethyl acetate. The combined organic layerswere washed with 2×30 mL of brine, dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with PE/EA (1:1) to yield ethyl3-(4-(4,4,5,5,5-pentafluoro-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)pentyl)benzamido)propanoateas yellow oil. LC-MS (ES, m/z) 641 [M+H]⁺.

Step 6. Preparation of3-(4-(4,4,5,5,5-pentafluoro-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)pentyl)benzamido)propanoicacid

Into a 25-mL round-bottom flask, was placed a solution of ethyl3-(4-(4,4,5,5,5-pentafluoro-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)pentyl)benzamido)propanoate(245 mg, 0.38 mmol, 1.00 equiv) in tetrahydrofuran/MeOH (8/2 mL) and asolution of LiOH.H₂O (161 mg, 3.83 mmol, 10.00 equiv) in water (2 mL).The resulting solution was stirred for 2 h at room temperature. The pHvalue of the solution was adjusted to pH2 with 2N HCl. The resultingsolution was extracted with 3×30 mL of ethyl acetate. The combinedorganic layers were washed with 2×30 mL of brine, dried over sodiumsulfate and concentrated under vacuum. The resulting residue (200 mg)was purified by Prep-HPLC with the following conditions (1#-Waters2767-1): Column, SunFire Prep C18, 5 um, 19*150 mm; mobile phase: waterin 0.05% TFA and CH₃CN (35% CH₃CN up to 80% in 10 min, up to 100% in 2min, down to 35% in 2 min) Detector, UV 254 nm to yield3-(4-(4,4,5,5,5-pentafluoro-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)pentyl)benzamido)propanoicacid as an off-white solid.

¹H NMR (300 MHz, CD₃OD) δ (ppm) 7.92 (d, J=0.9 Hz, 1H), 7.69-7.85 (m,6H), 7.58 (d, J=3.3 Hz, 1H), 7.40-7.53 (m, 4H), 6.72 (d, J=3.3 Hz, 1H),5.81-5.86 (m, 1H), 3.60 (t, J=6.9 Hz, 2H), 2.67-2.78 (m, 2H), 2.57 (t,J=6.9 Hz, 2H), 2.09-2.27 (m, 1H), 1.99-2.08 (m, 1H), LC-MS (ES, m/z) 613[M+H]⁺.

Example 31—Compound #363-(4-(3-Cyclobutyl-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)propyl)benzamido)propanoicacid

Step 1. Preparation of 3-cyclobutylpropan-1-ol

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of lithium aluminiumtetrahydride (2.2 g, 17.19 mmol, 1.50 equiv) in ethyl ether (60 mL). Tothe flask was then a solution of 3-cyclobutylpropanoic acid (5 g, 131.58mmol, 1.00 equiv) in ethyl ether (40 mL) dropwise with stirring at 0° C.The resulting solution was stirred overnight at room temperature. Thereaction was then quenched by the addition of 2.3 mL of water, 7 mL ofsodium hydroxide (15%) and 2.3 mL of water. The solids were filteredout. The filtrate was dried over anhydrous sodium sulfate andconcentrated under vacuum to yield 3-cyclobutylpropan-1-ol as yellowoil.

Step 2. Preparation of (3-bromopropyl)cyclobutane

Into a 250-mL round-bottom flask, was placed 3-cyclobutylpropan-1-ol(5.3 g, 46.49 mmol, 1.00 equiv), pyridine (1.1 g, 13.92 mmol, 0.30equiv). To the flask was then added tribromophosphine (5.3 g, 19.63mmol, 0.42 equiv) dropwise with stirring at 0° C. The resulting solutionwas stirred overnight at room temperature. The reaction was thenquenched by the addition of water/ice. The resulting solution wasextracted with 3×150 mL of ethyl ether. The combined organic layers werewashed with 3×150 mL of brine, dried over anhydrous sodium sulfate andconcentrated under vacuum to yield (3-bromopropyl)cyclobutane as yellowoil.

Step 3. Preparation of methyl 4-(3-cyclobutylpropyl)benzoate

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of(3-bromopropyl)cyclobutane (5 g, 28.41 mmol, 3.00 equiv) in1,3-dimethyl-tetrahydropyrimidin-2(1H)-one (15 mL), methyl4-iodobenzoate (2.48 g, 9.47 mmol, 1.00 equiv), NiI₂.6H₂O (398 mg, 0.95mmol, 0.10 equiv), 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine(127 mg, 0.47 mmol, 0.05 equiv), 1,2-bis(diphenylphosphino)benzene (211mg, 0.47 mmol, 0.05 equiv), manganese (1.042 g, 18.95 mmol, 2.00 equiv)and pyridine (75 mg, 0.95 mmol, 0.10 equiv). The resulting solution wasstirred overnight at 85° C. in an oil bath and then diluted with 100 mLof H₂O. The resulting solution was extracted with 3×100 mL of ethylacetate. The combined organic layers were washed with 2×100 mL of brine,dried over anhydrous sodium sulfate and concentrated under vacuum. Theresidue was applied onto a silica gel column and eluted with ethylacetate/petroleum ether (1:100-1:10) to yield methyl4-(3-cyclobutylpropyl)benzoate as yellow oil.

Step 4. Preparation of methyl 4-(1-bromo-3-cyclobutylpropyl)benzoate

Into a 250-mL round-bottom flask, was placed methyl4-(3-cyclobutylpropyl)benzoate (1 g, 4.31 mmol, 1.00 equiv),N-bromosuccinimide (770 mg, 4.33 mmol, 1.00 equiv), benzoyl peroxide (52mg, 0.21 mmol, 0.05 equiv) and carbon tetrachloride (80 mL). Theresulting solution was heated to reflux for 4 h and then cooled to roomtemperature. The solids were filtered out. The filtrate was concentratedunder vacuum. The residue was purified by a silica gel column with ethylacetate/petroleum ether (1:30) to yield methyl4-(1-bromo-3-cyclobutylpropyl)benzoate as yellow oil.

Step 5. Preparation of methyl4-(3-cyclobutyl-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)propyl)benzoate

Into a 50-mL round-bottom flask, was placed a solution of sodium hydride(37 mg, 0.93 mmol, 1.20 equiv, 60%) in DMF (5 mL). To the flask was thena solution of 5-(4-(trifluoromethyl)phenyl)-1H-indole (200 mg, 0.77mmol, 1.00 equiv) in DMF (5 mL) at 0° C. The mixture was stirred for 1 hat 0° C. To this was added a solution of methyl4-(1-bromo-3-cyclobutylpropyl)benzoate (309 mg, 1.00 mmol, 1.30 equiv)in DMF (10 mL) at the same temperature. The reaction mixture was stirredovernight at room temperature and then the reaction was quenched by theaddition of 30 mL of water. The resulting solution was extracted with3×20 mL of ethyl acetate. The combined organic layers were washed with3×30 mL of brine, dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was purified by a silica gel column with ethylacetate/petroleum ether (1:100-1:10) to yield methyl4-(3-cyclobutyl-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)propyl)benzoateas yellow oil.

Step 6. Preparation of4-(3-cyclobutyl-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)propyl)benzoicacid

Into a 50-mL round-bottom flask, was placed a solution of methyl4-(3-cyclobutyl-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)propyl)benzoate(100 mg, 0.20 mmol, 1.00 equiv) in tetrahydrofuran (4 mL), a solution ofLiOH.H₂O (86 mg, 2.05 mmol, 10.00 equiv) in water (1 mL) and methanol (1mL). The resulting solution was stirred overnight at room temperatureand then diluted with 30 mL of H₂O. The pH value of the solution wasadjusted to pH 2 with 3N HCl. The resulting solution was extracted with3×20 mL of ethyl acetate. The combined organic layers were washed with2×30 mL of brine, dried over sodium dulfate and concentrated undervacuum to yield4-(3-cyclobutyl-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)propyl)benzoicacid as yellow oil.

Step 7. Preparation of ethyl3-(4-(3-cyclobutyl-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)propyl)benzamido)propanoate

Into a 50-mL round-bottom flask, was placed a solution of4-(3-cyclobutyl-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)propyl)benzoicacid (80 mg, 0.17 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL) and2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (127 mg, 0.33 mmol, 2.00 equiv). To the flask wasthen added N,N-diisopropylethylamine (86 mg, 0.67 mmol, 4.00 equiv) andethyl 3-aminopropanoate hydrochloride (31 mg, 0.20 mmol, 1.20 equiv).The resulting solution was stirred overnight at room temperature andthen diluted with 30 mL of H₂O. The resulting solution was extractedwith 3×20 mL of ethyl acetate. The combined organic layers were washedwith 3×30 mL of brine, dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with ethyl acetate/petroleum ether (1:50-1:3) to yieldethyl3-(4-(3-cyclobutyl-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)propyl)benzamido)propanoateas yellow oil.

Step 8. Preparation of3-(4-(3-cyclobutyl-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)propyl)benzamido)propanoicacid

Into a 50-mL round-bottom flask, was placed a solution of ethyl3-(4-(3-cyclobutyl-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)propyl)benzamido)propanoate(80 mg, 0.14 mmol, 1.00 equiv) in tetrahydrofuran (4 mL), a solution ofLiOH.H₂O (58 mg, 1.38 mmol, 10.00 equiv) in water (1 mL) and methanol (1mL). The resulting solution was stirred overnight at room temperatureand then diluted with 20 mL of H₂O. The pH value of the solution wasadjusted to pH ˜2 with 1 N HCl. The resulting solution was extractedwith 3×20 mL of ethyl acetate. The combined organic layers were washedwith 2×30 mL of brine, dried over sodium sulfate and concentrated undervacuum. The resulting residue was purified by Prep-HPLC with thefollowing conditions (1#-Waters 2767-1): Column, SunFire Prep C18, 5 um,19*150 mm; mobile phase: water in 0.05% TFA and CH₃CN (50% CH₃CN up to75% in 10 min, up to 100% in 2 min, down to 50% in 2 min) Detector, UV254 nm to yield3-(4-(3-cyclobutyl-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)propyl)benzamido)propanoicacid as a white solid.

¹H-NMR (300 MHz, CDCl₃) δ 7.89 (s, 1H), 7.82 (d, J=8.1 Hz, 2H),7.68-7.76 (m, 4H), 7.56 (d, J=3.3 Hz, 1H), 7.41-7.48 (m, 2H), 7.35 (d,J=8.4 Hz, 2H), 6.66 (d, J=3.3 Hz, 1H), 5.61-5.66 (m, 1H), 3.61 (t, J=6.9Hz, 2H), 2.62 (t, J=6.9 Hz, 2H), 2.34-2.41 (m, 2H), 2.23 (s, 1H),2.06-2.12 (m, 2H), 1.81-1.90 (m, 2H), 1.55-1.64 (m, 2H), 1.43-1.47 (m,2H); LC-MS (ES, m/z) 549 [M+H]⁺.

Example 32—Compound #283-(4-(3-(4-Chlorophenyl)-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)propyl)benzamido)propanoicacid

Step 1. Preparation of 4-(3-(4-chlorophenyl)-1-hydroxypropyl)benzoicacid

Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of Mg (820 mg, 34.17mmol, 1.50 equiv) in tetrahydrofuran (10 mL). To the flask was thenadded a solution of 1-(2-bromoethyl)-4-chlorobenzene (5 g, 22.94 mmol,1.00 equiv) in tetrahydrofuran (50 mL) dropwise with stirring at roomtemperature in 30 min, this solution was stirred for 3 h at roomtemperature. To the resulting mixture was added a solution of4-formylbenzoic acid (1.1 g, 7.33 mmol, 0.32 equiv) in tetrahydrofuran(50 mL). The resulting solution was stirred overnight at roomtemperature. The resulting solution was diluted with 50 mL of H₂O. ThepH value of the solution was adjusted to pH 4-5 with 1N HCl. Theresulting solution was extracted with 3×50 mL of ethyl acetate. Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn and eluted with ethyl acetate/petroleum ether (1:1) to yield4-(3-(4-chlorophenyl)-1-hydroxypropyl)benzoic acid as a light yellowsolid. LC-MS (ES, m/z) 289 [M−H]⁻.

Step 2. Preparation of ethyl2-(4-(3-(4-chlorophenyl)-1-hydroxypropyl)benzamido)acetate

Into a 100-mL round-bottom flask, was placed a solution of4-(3-(4-chlorophenyl)-1-hydroxypropyl)benzoic acid (1 g, 3.45 mmol, 1.00equiv) in N,N-dimethylformamide (5 mL), HATU (2.6 g, 6.84 mmol, 2.00equiv), DIEA (1.78 g, 13.80 mmol, 4.00 equiv) and ethyl3-aminopropanoate hydrochloride (633 mg, 4.14 mmol, 1.20 equiv). Theresulting mixture was stirred overnight at room temperature and thenquenched by the addition of 50 mL of water. The resulting solution wasextracted with 3×50 mL of ethyl acetate. The combined organic layerswere dried over anhydrous sodium sulfate and concentrated under vacuum.The residue was purified by a silica gel column with ethylacetate/petroleum ether (1:3) to yield ethyl3-(4-(3-(4-chlorophenyl)-1-hydroxypropyl)benzamido)propanoate as a lightyellow solid. LC-MS (ES, m/z) 376 [M+H]⁺.

Step 3. Preparation of ethyl2-(4-(1-bromo-3-(4-chlorophenyl)propyl)benzamido)acetate

Into a 250-mL round-bottom flask, was placed a solution of ethyl3-(4-(3-(4-chlorophenyl)-1-hydroxypropyl)benzamido)propanoate (1.0 g,2.57 mmol, 1.00 equiv) in dichloromethane (100 mL). To the flask wasthen added PBr₃ (1.83 g, 6.78 mmol, 1.65 equiv) dropwise with stirringat 0° C. in 5 min. The resulting solution was stirred overnight at roomtemperature and then quenched by the addition of 50 mL of water. Theresulting solution was extracted with 3×50 mL of dichloromethane. Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:4) to yield ethyl3-(4-(1-bromo-3-(4-chlorophenyl)propyl)benzamido)propanoate as colorlessoil. LC-MS (ES, m/z) 440 [M+H]⁺.

Step 4. Preparation of ethyl3-(4-(3-(4-chlorophenyl)-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)propyl)benzamido)propanoate

Into a 50-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of sodium hydride(18.38 mg, 0.77 mmol, 2.00 equiv) in N,N-dimethylformamide (0.5 mL), asolution of 5-(4-(trifluoromethyl)phenyl)-1H-indole (100 mg, 0.38 mmol,1.00 equiv) in N,N-dimethylformamide (0.5 mL), and the solution wasstirred for 1 h at 0° C. To the resulting mixture was then added asolution of ethyl3-(4-(1-bromo-3-(4-chlorophenyl)propyl)benzamido)propanoate (224 mg,0.50 mmol, 1.30 equiv) in N,N-dimethylformamide (1 mL). The resultingsolution was stirred overnight at room temperature and then quenched bythe addition of 10 mL of water. The pH value of the solution wasadjusted to pH 4-5 with 1 N HCl. The resulting solution was extractedwith 3×15 mL of ethyl acetate. The combined organic layers were driedover anhydrous sodium sulfate and concentrated under vacuum. The residuewas applied onto a silica gel column and eluted with ethylacetate/petroleum ether (1:4-1:2) to yield ethyl3-(4-(3-(4-chlorophenyl)-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)propyl)benzamido)propanoateacid as light yellow oil. LC-MS (ES, m/z) 633 [M+H]⁺.

Step 5. Preparation of3-(4-(3-(4-chlorophenyl)-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)propyl)benzamido)propanoicacid

Into a 100-mL round-bottom flask, was placed a solution of ethyl3-(4-(3-(4-chlorophenyl)-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)propyl)benzamido)propanoate(160 mg, 0.29 mmol, 1.00 equiv, 100%) in tetrahydrofuran (4 mL), asolution of LiOH.H₂O (122.6 mg, 2.92 mmol, 10.00 equiv, 100%) inmethanol/H₂O (1/1 mL). The resulting solution was stirred overnight atroom temperature. The reaction was then quenched by the addition of 20mL of water. The pH value of the solution was adjusted to pH2 with 1NHCl. The resulting solution was extracted with 3×20 mL of ethyl acetate.The combined organic layers were dried over anhydrous sodium sulfate andconcentrated under vacuum. The resulting residue (180 mg) was purifiedby Prep-HPLC with the following conditions (1#-Waters 2767-1): Column,SunFire Prep C18, 5 um, 19*150 mm; mobile phase: water in 0.05% TFA andCH₃CN (40% CH₃CN up to 80% in 10 min, up to 100% in 2 min, down to 40%in 2 min) Detector, UV 254 nm to yield3-(4-(3-(4-chlorophenyl)-1-(5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)propyl)benzamido)propanoicacid as a white solid.

¹H-NMR (300 MHz, CD₃OD) δ (ppm) 7.92 (s, 1H), 7.82-7.84 (m, 2H),7.69-7.76 (m, 4H), 7.64 (s, 1H), 7.25-7.46 (m, 6H), 7.10-7.13 (m, 2H),6.71-6.72 (m, 1H), 5.61-5.63 (m, 1H), 3.58-3.63 (m, 2H), 2.60-2.80 (m,6H); LC-MS (ES, m/z) 605 [M+H]⁺.

Example 33—Compound #45(S)-3-(4-(1-(5-(2-Chloro-4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzamido)propanoicacid

Step 1: Preparation of methyl 4-(1-hydroxy-3-methylbutyl)benzoate

To a suspension of CuCN (1.64 g, 18.3 mmol) and LiCl (1.55 g, 36.7 mmol)in THF (20 ml) at −78° C. was added isobutylzinc bromide (50 ml, 0.5M).After it was stirred at −78° C. for 10 min, methyl 4-formylbenzoate(2.74 g, 16.7 mmol) and then BF₃.Et₂O (2.31 ml, 18.3 mmol) were added.The resulting mixture was stirred at −78° C. for 10 min, then at roomtemperature for 16 h. Saturated NH₄Cl solution was added and theresulting mixture extracted with EtOAc. The combined extracts werewashed brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel (EtOAc/heptane: 0>>>15%) to yield methyl4-(1-hydroxy-3-methylbutyl)benzoate as a white solid. ¹H NMR(CHLOROFORM-d) δ: 8.02 (d, J=8.3 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H),4.59-4.85 (m, 1H), 3.92 (s, 3H), 1.90 (d, J=3.7 Hz, 1H), 1.66-1.84 (m,2H), 1.49-1.56 (m, 1H), 1.24-1.38 (m, 1H), 1.09-1.20 (m, 1H), 0.87 (dd,J=6.6, 1.2 Hz, 6H).

Step 2: Preparation of methyl 4-(3-methylbutanoyl)benzoate

To a solution of methyl 4-(1-hydroxy-3-methylbutyl)benzoate (13.65 g,61.4 mmol) in dichloromethane (160 ml) was added PCC (14.6 g, 67.5 mmol)in portions and the mixture was stirred at room temperature for 16hours, then passed through a 120 g AnaLogix column, washed withEtOAc/heptane (3:1 v/v). The filtrate was concentrated to yield4-(3-methylbutanoyl)benzoate as a white solid. ¹H NMR (CHLOROFORM-d) δ:8.12 (d, J=8.3 Hz, 2H), 8.00 (d, J=8.3 Hz, 2H), 3.95 (s, 3H), 2.87 (d,J=6.8 Hz, 2H), 2.30 (dt, J=13.3, 6.8 Hz, 1H), 1.01 (d, J=6.6 Hz, 6H).

Step 3: Preparation of (R)-methyl 4-(1-hydroxy-3-methylbutyl)benzoate

To a solution of methyl 4-(3-methylbutanoyl)benzoate (6.00 g, 27.2 mmol)in THF (180 ml) was addedchloro((1R,2R,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)((1R,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)borane(11.65 g, 32.7 mmol) in portions at −78° C. under argon and the mixturewas stirred at −78° C. for 2 h, then warmed to room temperature and keptstirring for 16 h. The resulting mixture was quenched with MeOH and 1 mlof conc. HCl. The resulting mixture was then kept stirring for 3 h,neutralized with aq. NaHCO₃, extracted with EtOAc. The extracts werecombined and washed with brine, dried, filtered, and concentrated. Theresulting residue was purified by flash column chromatography on silicagel (EtOAc/heptane: 0>>>15%) to yield (R)-methyl4-(1-hydroxy-3-methylbutyl)benzoate. Diethanolamine (6.30 g, 59.9 mmol)was added to de-complex the B—O compound and the precipitate wasfiltered, washed with Et₂O. The filtrate was washed with 1N HCl, brine,dried over Na₂SO₄. The resulting residue was purified by flash columnchromatography on silica gel (EtOAc/heptane: 0>>>25%) to yield(R)-methyl 4-(1-hydroxy-3-methylbutyl)benzoate as a white solid (99%ee). ¹H NMR (CHLOROFORM-d) δ: 7.92-8.08 (m, 2H), 7.41 (d, J=8.1 Hz, 2H),4.81 (br d, J=4.9 Hz, 1H), 3.77-3.98 (m, 3H), 1.91-2.06 (m, 1H),1.67-1.78 (m, 2H), 1.42-1.56 (m, 1H), 0.96 (d, J=6.4 Hz, 6H).

Step 4: Preparation of (R)-methyl4-(3-methyl-1-((methylsulfonyl)oxy)butyl)benzoate

To a solution of (R)-methyl 4-(1-hydroxy-3-methylbutyl)benzoate (9.8 g,44.1 mmol) in 100 ml of dichloromethane was added trimethylamine (8.58ml, 61.7 mmol), followed by the addition of MsCl (4.11 ml, 52.9 mmol) at0° C. and the mixture was stirred at 0° C. for seven hours. Theresulting mixture was partitioned between 0.1 N HCl and DCM, then theextracts were washed with aq. NaHCO₃ four times, dried over Na₂SO₄,filtered, and concentrated under reduced pressure and further dried invacuo to yield (R)-methyl4-(3-methyl-1-((methylsulfonyl)oxy)butyl)benzoate as a white solid. ¹HNMR (CHLOROFORM-d) δ: 8.08 (d, J=7.6 Hz, 2H), 7.47 (d, J=7.6 Hz, 2H),5.63 (dd, J=8.7, 5.5 Hz, 1H), 3.93 (s, 3H), 2.68 (s, 3H), 2.03 (ddd,J=13.9, 8.3, 6.0 Hz, 1H), 1.72 (dt, J=13.0, 6.6 Hz, 1H), 1.56-1.66 (m,1H), 0.98 (t, J=6.7 Hz, 6H).

Step 5: Preparation of (S)-methyl4-(1-(5-(2-chloro-4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzoate

To a slurry of sodium hydride (32.6 mg, 0.82mmol)/5-(2-chloro-4-(trifluoromethyl)phenyl)-1H-indole (185.5 mg, 0.63mmol) was added 1 ml of DMF under argon and the mixture was stirred atroom temperature for 30 min. (R)-methyl4-(3-methyl-1-((methylsulfonyl)oxy)butyl)benzoate (245 mg, 0.82 mmol) in1 ml of DMF was added dropwise and the resulting mixture was stirred atroom temperature for 2 hours, quenched with 1N HCl, extracted withEtOAc. The organic layer was washed with brine, dried over Na₂SO₄,filtered, and concentrated to yield a brown oil, which was furtherpurified by flash column chromatography on silica gel (EtOAc/heptane:0>>>15%) to yield (S)-methyl4-(1-(5-(2-chloro-4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzoate.¹H NMR (CHLOROFORM-d) δ: 7.96 (d, J=8.1 Hz, 2H), 7.71 (d, J=15.6 Hz,2H), 7.44-7.56 (m, 2H), 7.31-7.41 (m, 2H), 7.20-7.28 (m, 3H), 6.65 (d,J=2.4 Hz, 1H), 5.63 (br dd, J=9.3, 6.1 Hz, 1H), 3.86 (s, 3H), 2.28-2.41(m, 1H), 1.98-2.12 (m, 1H), 1.47-1.65 (m, 1H), 0.99 (d, J=6.6 Hz, 6H).m/z (MH+): 500.0.

Step 6: Preparation of(S)-4-(1-(5-(2-chloro-4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzoicacid

To a solution of (S)-methyl4-(1-(5-(2-chloro-4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzoate(170 mg, 0.34 mmol) in THF/MeOH (4 ml, 3:1 v/v) was added 2 ml of 3MNaOH and the mixture was stirred at room temperature for 2 hours. Theresulting mixture was concentrated and the residue was acidified with 1NHCl, extracted with ethyl acetate. The combined organic layer was driedover Na₂SO₄, filtered and concentrated to yield(S)-4-(1-(5-(2-chloro-4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzoicacid as a white solid. ¹H NMR (CHLOROFORM-d) δ: 8.02 (d, J=8.3 Hz, 2H),7.67-7.76 (m, 2H), 7.47-7.56 (m, 2H), 7.40 (d, J=3.4 Hz, 1H), 7.33 (d,J=8.6 Hz, 1H), 7.28 (d, J=8.3 Hz, 2H), 7.20-7.25 (m, 1H), 6.67 (d, J=3.2Hz, 1H), 5.65 (dd, J=9.8, 5.9 Hz, 1H), 2.27-2.40 (m, 1H), 2.05-2.10 (m,1H), 1.59 (dt, J=13.6, 6.7 Hz, 1H), 1.01 (d, J=6.4 Hz, 6H). m/z (MH⁺):485.9.

Step 7: Preparation of (S)-methyl3-(4-(1-(5-(2-chloro-4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzamido)propanoate

To a mixture of(S)-4-(1-(5-(2-chloro-4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzoicacid (200 mg, 0.41 mmol), methyl 3-aminopropanoate (74.7 mg, 0.54 mmol),EDCl (102.6 mg, 0.54 mmol) and HOBt (63.0 mg, 0.41 mmol) was addeddiisopropylethylamine (0.22 ml, 1.24 mmol) and the reaction mixture wasstirred at room temperature for 4 hours, then concentrated. Theresulting residue was purified by flash column chromatography on silicagel (EtOAc/heptane: 0>>>20%) to yield (S)-methyl3-(4-(1-(5-(2-chloro-4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzamido)propanoateas a white solid. ¹H NMR (METHANOL-d₄) δ: 7.77 (s, 1H), 7.71 (d, J=8.3Hz, 2H), 7.52-7.65 (m, 4H), 7.46 (d, J=8.6 Hz, 1H), 7.34 (d, J=8.3 Hz,2H), 7.17 (dd, J=8.6, 1.7 Hz, 1H), 6.61 (d, J=3.2 Hz, 1H), 5.76 (dd,J=10.0, 5.6 Hz, 1H), 3.65 (s, 3H), 3.59 (t, J=6.8 Hz, 2H), 2.62 (t,J=6.8 Hz, 2H), 2.37-2.48 (m, 1H), 2.06 (ddd, J=14.2, 8.6, 5.6 Hz, 1H),1.52 (dquin, J=13.5, 6.6 Hz, 1H), 1.00 (dd, J=6.6, 3.2 Hz, 6H). m/z(MH+): 570.9.

Step 8: Preparation of(S)-3-(4-(1-(5-(2-Chloro-4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzamido)propanoicacid

To a solution of (S)-methyl3-(4-(1-(5-(2-chloro-4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzamido)propanoate(170 mg, 0.30 mmol) in THF/MeOH (4 ml, 3:1 v/v) was added 2 ml of 3MNaOH and the mixture was stirred at room temperature for 2 hours. Theresulting mixture was concentrated and the residue was acidified with 1NHCl, extracted with ethyl acetate. The combined organic layer was driedover Na₂SO₄, filtered and concentrated to yield(S)-3-(4-(1-(5-(2-Chloro-4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzamido)propanoicacid as a white solid.

¹H NMR (CHLOROFORM-d) δ: 10.70-11.23 (m, 1H), 7.72 (s, 1H), 7.67 (d,J=1.2 Hz, 1H), 7.62 (d, J=8.1 Hz, 2H), 7.49-7.55 (m, 1H), 7.44-7.48 (m,1H), 7.36 (d, J=3.4 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.15-7.23 (m, 3H),6.96 (br t, J=5.9 Hz, 1H), 6.63 (d, J=3.2 Hz, 1H), 3.62 (q, J=5.8 Hz,2H), 2.61 (br t, J=5.7 Hz, 1H), 2.57-2.67 (m, 1H), 2.29 (ddd, J=14.2,9.4, 5.5 Hz, 1H), 1.97-2.02 (m, 1H), 1.54 (dquin, J=13.5, 6.5 Hz, 1H),0.97 (dd, J=6.5, 1.8 Hz, 6H); m/z (MH⁺): 557.0.

Example 34—Compound #443-[[4-[1-[7-Fluoro-4-methyl-5-[2-methyl-4-(trifluoromethyl)phenyl]indol-1-yl]-3-methyl-butyl]benzoyl]amino]propanoicacid

Step 1: Preparation of ethyl4-(1-((4-bromo-2-fluoro-5-methylphenyl)imino)-3-methylbutyl)benzoate

To a solution of 4-bromo-2-fluoro-5-methylaniline (1.10 g, 5.39 mmol),ethyl 4-(3-methylbutanoyl)benzoate (1.26 g, 5.39 mmol) and Et₃N (2.25ml, 16.2 mmol) in DCM (100 ml) was added TiCl₄ (2.7 ml, 2.7 mmol)dropwise and the reaction was monitored by TLC. The mixture was keptstirring at room temperature for 16 h, then 5N NaOH was added to adjustpH=14, extracted with DCM and the organic layer was washed with brine,dried and concentrated. The resulting residue was used for the next stepreaction directly.

Step 2: Preparation of ethyl4-(1-((4-bromo-2-fluoro-5-methylphenyl)amino)-3-methylbutyl)benzoate

To a solution of the residue prepared in Step 1 above (1.70 g, 4.05mmol) in DCM (5 ml) was added NaBH(OAc)₃ (0.80 g, 3.78 mmol), followedby the addition of HOAc (0.1 ml) and the mixture was stirred at roomtemperature for 16 hours. NaBH₃CN (0.25 g, 4.18 mmol) and anhydrous THF(5 ml) were added and the reaction mixture was stirred for another 4hours. Upon the completion of the reaction, 3N NaOH was added and themixture was extracted with DCM. The organic layer was washed with brine,dried, filtered and concentrated to yield ethyl4-(1-((4-bromo-2-fluoro-5-methylphenyl)amino)-3-methylbutyl)benzoate. ¹HNMR (CHLOROFORM-d) δ: 8.00 (d, J=8.1 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H),7.11 (d, J=11.0 Hz, 1H), 6.22 (d, J=9.0 Hz, 1H), 4.33-4.44 (m, 3H), 4.24(br s, 1H), 2.11 (s, 3H), 1.83-1.90 (m, 1H), 1.67-1.78 (m, 1H),1.55-1.61 (m, 1H), 1.38 (t, J=7.1 Hz, 3H), 0.97 (dd, J=18.7, 6.0 Hz,6H).

Step 3: Preparation of ethyl4-(1-((4-bromo-6-fluoro-2-iodo-3-methylphenyl)amino)-3-methylbutyl)benzoate

To a solution of ethyl4-(1-((4-bromo-2-fluoro-5-methylphenyl)amino)-3-methylbutyl)benzoate(975 mg, 2.07 mmol) in acetonitrile (18 ml) was added NIS (450 mg, 2.0mmol), followed by the addition of 0.01 mL of TFA. The resulting mixturewas stirred at room temperature for 16 hours. The resulting mixture wasdiluted with EtOAc, washed with Na₂S₂O₃ solution and brine, dried andthe residue was purified by flash column chromatography on silica gel(EtOAc/heptane: 0>>>10%) to yield ethyl4-(1-((4-bromo-6-fluoro-2-iodo-3-methylphenyl)amino)-3-methylbutyl)benzoate.

Step 4: Preparation of ethyl4-(1-((4-bromo-6-fluoro-3-methyl-2-((trimethylsilyl)ethynyl)phenyl)amino)-3-methylbutyl)benzoate

To a solution of ethynyltrimethylsilane (295.6 mg, 3.01 mmol), ethyl4-(1-((4-bromo-6-fluoro-2-iodo-3-methylphenyl)amino)-3-methylbutyl)benzoate(1.10 g, 2.01 mmol), PdCl₂(PPh₃)₂ (42.3 mg, 0.06 mmol), and CuI (22.9mg, 0.12 mmol) in 10 ml of THF was added Et₃N (0.39 ml, 2.81 mmol) andthe resulting mixture was stirred at room temperature for 3 hours. TLCshowed one spot (complete conversion). The product was purified by flashcolumn chromatography on silica gel (EtOAc/heptanes: 0>>>10%) to yieldethyl4-(1-((4-bromo-6-fluoro-3-methyl-2-((trimethylsilyl)ethynyl)phenyl)amino)-3-methylbutyl)benzoate.¹H NMR (CHLOROFORM-d) δ: 7.94 (br d, J=8.1 Hz, 2H), 7.21-7.34 (m, 3H),6.92-7.08 (m, 1H), 4.71-4.98 (m, 1H), 4.30-4.40 (m, 2H), 2.39 (s, 3H),1.65-1.83 (m, 2H), 1.36 (t, J=7.1 Hz, 3H), 1.30 (br s, 1H), 0.97 (t,J=5.6 Hz, 6H), 0.33 (s, 9H).

Step 5: Preparation of ethyl4-(1-((5-fluoro-2,2′-dimethyl-4′-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)-[1,1′-biphenyl]-4-yl)amino)-3-methylbutyl)benzoate

To a 20 ml vial was added ethyl4-(1-((4-bromo-6-fluoro-3-methyl-2-((trimethylsilyl)ethynyl)phenyl)amino)-3-methylbutyl)benzoate(129.8 mg, 0.64 mmol), followed by the addition of2-methyl-4-trifluoromethylphenyl boronic acid (129.8 mg, 0.64 mmol),PdCl₂(dppf) (18.1 mg, 0.025 mmol) and Cs₂CO₃ (135.7 mg, 0.42 mmol) wasadded 2 ml of 1,4-dioxane and the vial was sealed and heated at 90° C.for 16 h. The volatile was removed under reduced pressure and theresidue was purified by flash column chromatography on silica gel(EtOAc/heptane: 0>>>10%) to yield ethyl4-(1-((5-fluoro-2,2′-dimethyl-4′-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)-[1,1′-biphenyl]-4-yl)amino)-3-methylbutyl)benzoate.¹H NMR (CHLOROFORM-d) δ: 7.86-7.94 (m, 2H), 7.28-7.45 (m, 4H), 6.96-7.08(m, 1H), 6.42-6.55 (m, 1H), 4.87-5.03 (m, 1H), 4.70-4.86 (m, 1H),4.25-4.34 (m, 2H), 1.86-2.04 (m, 7H), 1.61-1.77 (m, 1H), 1.27-1.34 (m,4H), 0.90-0.98 (m, 6H), 0.26 (d, J=1.5 Hz, 9H).

Step 6: Preparation of ethyl4-(1-(7-fluoro-4-methyl-5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzoate

To a 20 ml vial was added ethyl4-(1-((5-fluoro-2,2′-dimethyl-4′-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)-[1,1′-biphenyl]-4-yl)amino)-3-methylbutyl)benzoate(150 mg, 0.26 mmol), followed by the addition of CaCO₃ (25.7 mg, 0.26mmol), CuI (24.5 mg, 0.13 mmol) and 1 ml of DMF. The vial was sealedwith a TFE cap and the mixture was stirred at 120° C. for 2 hours,cooled to room temperature. The resulting mixture was washed with water,extracted with EtOAc. The organic layer was washed with brine, dried andpurified by flash column chromatography on silica gel (EtOAc/heptane:0>>>20%) to yield ethyl4-(1-(7-fluoro-4-methyl-5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzoate.¹H NMR (CHLOROFORM-d) δ: 7.97 (d, J=8.1 Hz, 2H), 7.65 (br d, J=7.8 Hz,2H), 7.44 (br d, J=8.1 Hz, 2H), 7.37 (br s, 1H), 7.29 (s, 2H), 6.77 (d,J=13.7 Hz, 1H), 6.66 (br s, 1H), 6.00-6.10 (m, 1H), 4.32-4.40 (m, 2H),2.39 (s, 3H), 2.25-2.34 (m, 1H), 2.02 (dt, J=14.0, 7.1 Hz, 1H),1.60-1.66 (m, 1H), 1.35 (t, J=7.1 Hz, 3H), 1.02 (t, J=6.6 Hz, 6H).

Step 7: Preparation of4-(1-(7-fluoro-4-methyl-5-(2-methyl-4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzoicacid

To a solution of ethyl4-(1-(7-fluoro-4-methyl-5-(4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzoate(70 mg, 0.13 mmol) in 3 ml of THF/MeOH (2:1 v/v) was added 1 ml of LiOH(1M) and the reaction mixture was stirred at room temperature for 2hours, then concentrated under reduced pressure. The resulting mixturewas acidified with 1N HCl (pH 4), extracted with EtOAc. The organicextracts were washed with brine, dried over Na₂SO₄, filtered, andconcentrated to yield4-(1-(7-fluoro-4-methyl-5-(2-methyl-4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzoicacid as a white foam solid, which was used for the next step reactiondirectly.

Step 8: Preparation of methyl3-(4-(1-(7-fluoro-4-methyl-5-(2-methyl-4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzamido)propanoate

To a mixture of4-(1-(7-fluoro-4-methyl-5-(2-methyl-4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzoicacid (34 mg, 0.068 mmol), methyl 3-aminopropanoate hydrogen chloride(14.3 mg, 0.10 mmol), HATU (39 mg, 0.10 mmol) in DCM (2.9 ml) was addedDIEA (0.018 ml) and the reaction mixture was stirred at room temperaturefor 16 h. The solvent was removed under reduced pressure and the residuewas purified by flash column chromatography on silica gel(EtOAc/heptane: 0>>>70%) to yield methyl3-(4-(1-(7-fluoro-4-methyl-5-(2-methyl-4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzamido)propanoate.

Step 9: Preparation of3-[[4-[1-[7-fluoro-4-methyl-5-[2-methyl-4-(trifluoromethyl)phenyl]indol-1-yl]-3-methyl-butyl]benzoyl]amino]propanoicacid

To a solution of methyl3-(4-(1-(7-fluoro-4-methyl-5-(2-methyl-4-(trifluoromethyl)phenyl)-1H-indol-1-yl)-3-methylbutyl)benzamido)propanoate(70 mg, 0.13 mmol) in 3 ml of THF/MeOH (2:1 v/v) was added 1 ml of LiOH(1M) and the reaction mixture was stirred at room temperature for 2hours, then concentrated under reduced pressure. The resulting mixturewas acidified with 1N HCl (pH 4), extracted with EtOAc. The organicextracts were washed with brine, dried over Na₂SO₄, filtered, andconcentrated to yield a white foam solid, which was further purified byreverse-phase HPLC to yield−[[4-[1-[7-fluoro-4-methyl-5-[2-methyl-4-(trifluoromethyl)phenyl]indol-1-yl]-3-methyl-butyl]benzoyl]amino]propanoicacid.

¹H NMR (METHANOL-d₄) δ: 7.74 (dd, J=7.8, 4.8 Hz, 2H), 7.60-7.65 (m, 1H),7.57 (br d, J=5.6 Hz, 1H), 7.50 (br t, J=8.1 Hz, 1H), 7.24-7.39 (m, 3H),6.68 (br s, 1H), 6.60 (dd, J=13.6, 4.5 Hz, 1H), 6.06 (br s, 1H), 3.60(br t, J=6.8 Hz, 2H), 2.60 (br t, J=6.6 Hz, 2H), 2.37-2.50 (m, 1H),2.00-2.19 (m, 7H), 1.59 (br d, J=6.1 Hz, 1H), 1.01-1.12 (m, 6H); m/z(MH⁺): 569.3.

Example 35—Compound #243-[[4-[1-[6-Chloro-5-[2-chloro-4-(trifluoromethyl)phenyl]indol-1-yl]-3-methyl-butyl]benzoyl]amino]propanoicacid

¹H NMR (CHLOROFORM-d) δ: 7.73 (dd, J=5.1, 1.2 Hz, 1H), 7.68 (d, J=8.3Hz, 2H), 7.52-7.59 (m, 1H), 7.46 (d, J=2.9 Hz, 1H), 7.35-7.45 (m, 3H),7.22 (dd, J=12.5, 8.3 Hz, 2H), 6.93 (q, J=5.6 Hz, 1H), 6.59 (d, J=3.2Hz, 1H), 5.53 (dd, J=9.4, 6.2 Hz, 1H), 3.68 (q, J=5.4 Hz, 2H), 2.66 (brt, J=5.0 Hz, 2H), 2.29 (ddd, J=14.3, 9.2, 5.6 Hz, 1H), 2.04 (m, 1H),1.56 (qd, J=13.7, 6.6 Hz, 1H), 0.97-1.03 (m, 6H); m/z (MH⁺): 593.1.

Example 36—Compound #253-[[4-[1-[6-Chloro-5-[2-methyl-4-(trifluoromethyl)phenyl]indol-1-yl]-3-methyl-butyl]benzoyl]amino]propanoicacid

¹H NMR (CHLOROFORM-d) δ: 7.69 (br t, J=7.3 Hz, 2H), 7.44-7.54 (m, 2H),7.34-7.42 (m, 3H), 7.19-7.31 (m, 4H), 6.85 (br s, 1H), 6.58 (d, J=2.7Hz, 1H), 5.53 (br dd, J=8.9, 6.5 Hz, 1H), 3.70 (br d, J=4.4 Hz, 2H),2.68 (br s, 2H), 2.25-2.36 (m, 1H), 2.05 (s, 3H), 2.00-2.09 (m, 1H),1.48-1.66 (m, 1H), 1.01 (br t, J=6.0 Hz, 6H).

Example 37—Compound #353-[[4-[1-[5-[2-Chloro-4-(trifluoromethyl)phenyl]-6-methoxy-indol-1-yl]-3-methyl-butyl]benzoyl]amino]propanoicacid

¹H NMR (METHANOL-d₄) δ: 7.71-7.78 (m, 3H), 7.56-7.61 (m, 1H), 7.42-7.51(m, 2H), 7.34-7.40 (m, 2H), 7.31 (s, 1H), 6.97-7.01 (m, 1H), 6.42-6.59(m, 1H), 5.65-5.86 (m, 1H), 3.71 (s, 3H), 3.54-3.63 (m, 2H), 2.60 (t,J=7.1 Hz, 2H), 2.37-2.48 (m, 1H), 2.02-2.12 (m, 1H), 1.56 (br s, 1H),1.03 (t, J=6.6 Hz, 6H); m/z (MH⁺): 587.1.

Example 38—Compound #423-[[4-[1-[7-Fluoro-4-methyl-5-[4-(trifluoromethyl)phenyl]indol-1-yl]-3-methyl-butyl]benzoyl]amino]propanoicacid

¹H NMR (METHANOL-d₄) δ: 7.72 (dd, J=14.9, 8.3 Hz, 4H), 7.61 (d, J=3.0Hz, 1H), 7.52 (d, J=7.6 Hz, 2H), 7.31 (d, J=8.6 Hz, 2H), 6.62-6.82 (m,2H), 6.05 (dd, J=10.1, 5.6 Hz, 1H), 3.57 (t, J=6.8 Hz, 2H), 2.44 (t,J=6.8 Hz, 3H), 2.37 (s, 3H), 2.05 (ddd, J=14.1, 8.3, 5.8 Hz, 1H), 1.57(dt, J=13.5, 6.6 Hz, 1H), 1.02 (t, J=6.8 Hz, 6H); m/z (MH⁺): 555.2.

Example 39—Compound #433-[[4-[1-[5-(4-Chloro-2-methyl-phenyl)-7-fluoro-4-methyl-indol-1-yl]-3-methyl-butyl]benzoyl]amino]propanoicacid

¹H NMR (METHANOL-d₄) δ: 7.70-7.77 (m, 2H), 7.56-7.62 (m, 1H), 7.26-7.40(m, 3H), 7.15-7.24 (m, 1H), 6.99-7.10 (m, 1H), 6.62-6.67 (m, 1H),6.52-6.60 (m, 1H), 6.00-6.10 (m, 1H), 3.59 (t, J=6.8 Hz, 2H), 2.61 (t,J=6.8 Hz, 2H), 2.34-2.47 (m, 1H), 2.13 (s, 3H), 2.01 (d, J=22.7 Hz, 4H),1.49-1.69 (m, 1H), 1.02 (q, J=6.2 Hz, 6H); m/z (MH⁺): 535.2.

Example 40—Compound #463-[[4-[1-[5-[2-Chloro-4-(trifluoromethyl)phenyl]-7-fluoro-4-methyl-indol-1-yl]-3-methyl-butyl]benzoyl]amino]propanoicacid

¹H NMR (METHANOL-d₄) δ: 7.81 (br d, J=4.5 Hz, 1H), 7.74 (dd, J=7.6, 4.5Hz, 2H), 7.63 (dt, J=7.3, 3.9 Hz, 2H), 7.43-7.52 (m, 1H), 7.34 (dd,J=19.2, 8.1 Hz, 2H), 6.69 (br s, 2H), 5.98-6.15 (m, 1H), 3.59 (t, J=6.8Hz, 2H), 2.61 (t, J=6.8 Hz, 2H), 2.42 (br t, J=11.9 Hz, 1H), 2.20 (s,3H), 2.05 (dt, J=14.1, 7.1 Hz, 1H), 1.58 (dq, J=30.7, 6.8 Hz, 1H), 1.02(q, J=7.1 Hz, 6H); m/z (MH⁺): 589.2.

Example 41—Compound #73-[[4-[3-Methyl-1-[5-[4-(trifluoromethyl)phenyl]indol-1-yl]butyl]benzoyl]amino]propanoicacid

¹H NMR (CHLOROFORM-d) δ: 10.36-10.82 (m, 1H), 7.84 (d, J=1.0 Hz, 1H),7.58-7.73 (m, 6H), 7.28-7.42 (m, 3H), 7.18 (d, J=8.3 Hz, 2H), 6.76-6.85(m, 1H), 6.65 (d, J=2.9 Hz, 1H), 5.45-5.71 (m, 1H), 3.63 (br d, J=5.6Hz, 2H), 2.62 (br t, J=5.3 Hz, 2H), 2.26-2.40 (m, 1H), 1.95-2.04 (m,1H), 1.44-1.64 (m, 1H), 0.98 (d, J=6.4 Hz, 6H). m/z (MH⁺): 523.2.

Table 2 below lists the general synthesis scheme used in the preparationof representative compounds of the present invention

TABLE 2 ID No. Prepared According To 1 Scheme 1 2 Scheme 2 6 Scheme 2 7Scheme 1 9 Scheme 2 10 Scheme 1 11 Scheme 1 14 Scheme 1 15 Scheme 1 16Scheme 1 17 Scheme 1 18 Scheme 1 19 Scheme 1 21 Scheme 1 22 Scheme 1 23Scheme 1 24 Scheme 4 25 Scheme 4 26 Scheme 2 27 Scheme 2 28 Scheme 5 29Scheme 2 30 Scheme 2 31 Scheme 2 32 Scheme 2 33 Scheme 2 34 Scheme 2 35Scheme 4 36 Scheme 2 37 Scheme 2 38 Scheme 2 39 Scheme 2 40 Scheme 1 41Scheme 1 or 2 42 Scheme 4 43 Scheme 4 44 Scheme 4 45 Scheme 3 46 Scheme4 47 Scheme 1 48 Scheme 1

Biological Example 1—Prophetic Example Inhibition ¹²⁵I-Glucagon Bindingto Membranes from HEK293 Cells Expressing the Human Glucagon Receptor(GCGR)

Full-length human GCGR (Accession Number: NM000160) subcloned intopcDNA3.1 is stably transfected into HEK293 cells (hGluc-1HEK) andmaintained under G418 selection (500 μg/mL). Cell cultures aremaintained in DMEM/F12 media supplemented with 10% FBS and 1% GlutaMax™Supplement (Available from ThermoFisher Scientific, catalog #35050061).Membranes are prepared from these cells as follows: cells are harvestedfrom T225 flasks and re-suspended in hypotonic lysis buffer, 50 mM HEPESpH 7.4 supplemented with Complete Protease inhibitors (BoehringerMannheim, Indianapolis, Ind.). Cells are dounced 20 times on ice andspun at 700×g to remove nuclei and unlysed cells. The resulting pelletis re-suspended in hypotonic lysis buffer and the above step isrepeated. Supernatants from the low speed centrifugation are combinedand subsequently spun at 100K×g for 1 hr at 4° C. The resulting pelletis re-suspended in buffer containing 50 mM HEPES pH 7.4 and 10% sucrose,and the protein concentration is adjusted at 1 mg/mL as determined inthe Pierce™ BCA Protein Assay Kit (Available from ThermoFisherScientific, Catalog #23225). Membranes are aliquoted and stored at −80°C. The binding assay is performed by a filtration method in a 384 wellformat. Membranes at a final protein concentration of 6 μg/well areincubated with ¹²⁵I-glucagon at 0.3 nM and in the presence of compoundfor 2 hours at room temperature in a total reaction volume of 40 μL perwell. Assay buffer consists of 50 mM HEPES, pH 7.4, 5 mM MgCl₂, 1 mMCaCl₂ and 0.2% BSA. 30 μL of the reaction is then transferred to PEItreated filter plates and followed by filter aspiration. Plates are thenwashed 5× and allowed to dry at room temperature overnight. The next daythe bottom of the plate is covered with seal tape and scintillant wasadded. Total counts retained by the filters are quantified with a TopCount instrument. IC₅₀'s are generated by using a non-linear regressionmacro driven in Excel and converted to K_(i)'s.

Biological Example 2 IC₅₀ Values in Cellular Functional Assays: cAMPReadout

Full-length human GCGR (Accession Number: NM000160) subcloned intopcDNA3.1 was stably transfected into HEK293 cells (hGluc-1HEK) andmaintained under G418 selection (500 μg/mL). Cell cultures weremaintained in DMEM/F12 media supplemented with 10% FBS and 1% GlutaMax™Supplement (Available from ThermoFisher Scientific, catalog #35050061).Glucagon stimulated cAMP was quantified using LANCE technology as permanufacturer instructions. On the day of the experiment, spent media wasremoved and cells were washed with Hank's Buffered Saline solution(HBSS), and cells harvested with non-enzymatic cell dissociationsolution, then washed once with HBSS. Cells were re-suspended instimulation buffer at a concentration of 0.83×10⁶ cells/ml and cAMPdetection antibody was added. 6 μl/well of this solution was thendispensed in a 384 well plate (cell density 5000 cells/well). Testcompound was serially diluted in DMSO and 50 nl were dispensed on top ofthe cell solution and allowed to incubate for 30 minutes. 6 μl of a 2×glucagon solution (final concentration in assay 100 μM) was then addedand the reaction was terminated after 5 minutes with the addition ofdetection mix. The resulting mixture was incubated, protected from lightfor 1.5 h. cAMP levels were quantified by TR-FRET in an EnVisioninstrument against a known standard. IC₅₀'s were generated by using anon-linear regression macro driven in Excel and converted to K_(i)values.

Representative compounds of the present invention were tested accordingto the procedures as described in Biological Example 2, with results aslisted in Table 3, below.

TABLE 3 Biological Assay Results ID No. Glucagon cAMP Ki (μM) 1 0.11 20.37 6 0.18 7 0.07, 0.16 9 0.25 10 0.70 11 >5.20 14 0.085 15 0.14 160.12 17 0.15 18 0.17 19 0.10 21 0.60 22 0.65 23 0.55 24 0.14 25 0.10 260.13 27 0.18 28 0.55 29 0.35 30 0.21 31 0.37 32 0.27 33 0.24 34 0.19 350.10 36 0.13 37 0.48 38 0.31 39 0.50 40 0.10 41 2.30 42 0.85 43 0.90 440.70 45 0.12 46 1.15 47 0.27 48 0.045

Biological Example 3—Prophetic Example Glucagon Challenge In Vivo AssayMeasuring Blood Glucose

The efficacy of a glucagon receptor antagonist may be evaluated using anormal dog glucagon challenge test. Male beagle dogs are overnightfasted prior to the study. Test compound (at varying concentration ordosage) or vehicle (0.5% hydroxypropyl methylcellulose) is dosed viaoral gavage. Ninety minutes later, the dogs are submitted to a glucagonchallenge test by a single intramuscular injection of glucagon(Glucagon, rDNA origin, Eli Lilly, Indianapolis, Ind.) at dose of 5μg/kg. Blood glucose levels are determined at times −10 min, 0 min (onchallenge), 10 min, 20 min, 30 min, and 60 min after glucagon injection.

Formulation Example 1—Prophetic Example Solid, Oral Dosage Form

As a specific embodiment of an oral composition, 100 mg of Compound #6prepared as in Example 1, or compound #45 prepared as in Example 33 isformulated with sufficient finely divided lactose to provide a totalamount of 580 to 590 mg to fill a size O hard gel capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

We claim:
 1. A compound of formula (I)

wherein R¹ is selected from the group consisting of phenyl, naphthyl,thienyl, benzofuranyl, benzothienyl, indazolyl, quinolinyl, pyrazolyland pyridyl; wherein the phenyl, naphthyl, thienyl, benzofuranyl,benzothienyl, indazolyl, quinolinyl, pyrazolyl or pyridyl whether aloneor as part of a substituent group is optionally substituted with one tomore substituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy and fluorinatedC₁₋₄alkoxy; a is an integer from 0 to 2; each R² is independentlyselected from the group consisting of halogen, C₁₋₄alkyl, fluorinatedC₁₋₄alkyl, C₁₋₄alkoxy and fluorinated C₁₋₄alkoxy; R³ is selected fromthe group consisting of hydrogen, C₁₋₄alkyl and phenyl; R⁴ is selectedfrom the group consisting of C₁₋₆alkyl, fluorinated C₁₋₄alkyl,—(C₁₋₂alkyl)-O—(C₁₋₄alkyl), C₃₋₆cycloalkyl, —(C₁₋₂alkyl)-C₃₋₆cycloalkyl,phenyl and —(C₁₋₂alkyl)-phenyl; wherein the phenyl, whether alone or aspart of a substituent group is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy and fluorinatedC₁₋₄alkoxy; Z is selected from the group consisting of C and N; or astereoisomer or pharmaceutically acceptable salt thereof.
 2. A compoundof claim 1, wherein R¹ is selected from the group consisting of phenyl,naphthyl, thienyl, pyridyl, benzofuranyl, benzothienyl, indazolyl,pyrazolyl and quinolinyl; wherein the phenyl, naphthyl, benzofuranyl,benzothienyl, indazolyl or pyrazolyl is optionally substituted with oneto two substituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, fluorinated C₁₋₂alkyl, C₁₋₂alkoxy and fluorinatedC₁₋₂alkoxy; a is an integer from 0 to 2; each R² is independentlyselected from the group consisting of halogen, C₁₋₄alkyl, fluorinatedC₁₋₂alkyl, C₁₋₄alkoxy and fluorinated C₁₋₂alkoxy; R³ is selected fromthe group consisting of hydrogen, methyl and phenyl; R⁴ is selected fromthe group consisting of C₁₋₆alkyl, fluorinated C₁₋₄alkyl,—(C₁₋₂alkyl)-O—(C₁₋₄alkyl), C₃₋₆cycloalkyl, —(C₁₋₂alkyl)-C₃₋₆cycloalkyl,phenyl and —(C₁₋₂alkyl)-phenyl; wherein the phenyl, whether alone or aspart of a substituent group is optionally substituted with one or to twosubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, fluorinated C₁₋₂alkyl, C₁₋₄alkoxy and fluorinatedC₁₋₂alkoxy; Z is selected from the group consisting of C and N; or astereoisomer or pharmaceutically acceptable salt thereof.
 3. A compoundof claim 2, wherein R¹ is selected from the group consisting of phenyland benzothienyl; wherein the phenyl or benzothienyl is optionallysubstituted with one to two substituents independently selected from thegroup consisting of halogen, C₁₋₄alkyl and fluorinated C₁₋₂alkyl; a isan integer from 0 to 2; each R² is independently selected from the groupconsisting of halogen, C₁₋₂alkyl, fluorinated C₁₋₂alkyl and C₁₋₂alkoxy;R³ is selected from the group consisting of hydrogen and phenyl; R⁴ isselected from the group consisting of C₁₋₆alkyl, fluorinated C₁₋₄alkyl,—(C₁₋₂alkyl)-O—(C₁₋₂alkyl), C₃₋₆cycloalkyl, —(C₁₋₂alkyl)-C₃₋₆cycloalkyl,—(C₁₋₂alkyl)-phenyl; wherein the phenyl is optionally substituted with ahalogen; Z is selected from the group consisting of C and N; or astereoisomer or pharmaceutically acceptable salt thereof.
 4. A compoundof claim 3, wherein R¹ is selected from the group consisting of4-t-butylphenyl, 4-trifluoromethyl-phenyl, 2,4-dichloro-phenyl,2-methyl-4-chloro-phenyl, 2-methyl-4-trifluoromethyl-phenyl,2-chloro-4-trifluoromethyl-phenyl, benzothien-2-yl and6-fluoro-benzothien-2-yl; a is an integer from 0 to 1; and R² isselected from the group consisting of 6-chloro, 6-methyl, 6-methoxy and6-trifluoromethyl; alternatively, a is 2; and the two R² groups are4-methyl and 7-fluoro; R³ is selected from the group consisting ofhydrogen and phenyl; R⁴ is selected from the group consisting ofn-propyl, 3,3,3-trifluoro-n-propyl, isobutyl, 2-fluoro-isobutyl,4,4,4-trifluoro-n-butyl, 3,3,4,4,4-pentafluoro-n-butyl, n-pentyl,isopentyl, n-hexyl, methoxy-ethyl, cyclopropyl-methyl-,cyclobutyl-ethyl-, cyclopentyl-ethyl-, cyclohexyl, cyclohexyl-methyl-,cyclohexyl-ethyl-, phenylethyl- and 4-chlorophenyl-ethyl-; Z is selectedfrom the group consisting of C and N; or a stereoisomer orpharmaceutically acceptable salt thereof.
 5. A compound of claim 4,wherein R¹ is selected from the group consisting of 4-t-butylphenyl,4-trifluoromethyl-phenyl, 2,4-dichloro-phenyl,2-methyl-4-trifluoromethyl-phenyl, 2-chloro-4-trifluoromethyl-phenyl,benzothien-2-yl and 6-fluoro-benzothien-2-yl, a is an integer from 0 to1; and R² is selected from the group consisting of 6-chloro, 6-methyland 6-methoxy; R³ is hydrogen; R⁴ is selected from the group consistingof n-propyl, isobutyl, n-pentyl, n-hexyl, cyclobutyl-ethyl-,cyclopentyl-ethyl-, cyclohexyl, cyclohexyl-methyl- andcyclohexyl-ethyl-; Z is selected from the group consisting of C and N;or a stereoisomer or pharmaceutically acceptable salt thereof.
 6. Acompound of claim 4, wherein R¹ is selected from the group consisting of4-t-butylphenyl, 4-trifluoromethyl-phenyl,2-methyl-4-trifluoromethyl-phenyl, 2-chloro-4-trifluoromethyl-phenyl,benzothien-2-yl and 6-fluoro-benzothien-2-yl; a is an integer from 0 to1; and R² is selected from the group consisting of 6-chloro, 6-methyland 6-methoxy; R³ is hydrogen; R⁴ is selected from the group consistingof isobutyl, n-hexyl, cyclobutyl-ethyl-, cyclohexyl andcyclohexyl-ethyl-; Z is C; or a stereoisomer or pharmaceuticallyacceptable salt thereof.
 7. A compound of claim 4, wherein R¹ isselected from the group consisting of 4-trifluoromethyl-phenyl,2-methyl-4-trifluoromethyl-phenyl and 2-chloro-4-trifluoromethyl-phenyl;a is an integer from 0 to 1; and R² is selected from the groupconsisting of 6-chloro, 6-methyl and 6-methoxy; R³ is hydrogen; R⁴ isselected from the group consisting of isobutyl and cyclohexyl; Z is C;or a stereoisomer or pharmaceutically acceptable salt thereof.
 8. Acompound of claim 4, selected from the group consisting of R¹ isselected from the group consisting of 4-trifluoromethyl-phenyl,2-methyl-4-trifluoromethyl-phenyl and 2-chloro-4-trifluoromethyl-phenyl;a is an integer from 0 to 1; and R² is 6-methoxy; R³ is hydrogen; R⁴ isisobutyl; Z is selected from the group consisting of C and N; anstereoisomers and pharmaceutically acceptable salts thereof.
 9. Acompound of claim 4 selected from the group consisting of3-[[5-[3-methyl-1-[5-[4-(trifluoromethyl)phenyl]indol-1-yl]butyl]pyridine-2-carbonyl]amino]propanoicacid;3-[[4-[3-methyl-1-[5-[4-(trifluoromethyl)phenyl]indol-1-yl]butyl]benzoyl]amino]propanoicacid;3-[[4-[3-methyl-1-[5-[2-methyl-4-(trifluoromethyl)phenyl]indol-1-yl]butyl]benzoyl]amino]propanoicacid;3-[[4-[1-[5-[2-chloro-4-(trifluoromethyl)phenyl]-6-methoxy-indol-1-yl]-3-methyl-butyl]benzoyl]amino]propanoicacid;3-[[4-[(1S)-1-[5-[2-chloro-4-(trifluoromethyl)phenyl]indol-1-yl]-3-methyl-butyl]benzoyl]amino]propanoicacid; and stereoisomers and pharmaceutically acceptable salts thereof;10. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound of claim
 1. 11. The pharmaceuticalcomposition of claim 10, wherein the carrier is selected from the groupconsisting of binders, suspending agents, lubricants, flavorants,sweeteners, preservatives, dyes, and coatings.
 12. The pharmaceuticalcomposition of claim 10, wherein said pharmaceutical composition is inan oral form.
 13. The pharmaceutical composition of claim 12, whereinthe oral form is a pill, tablet, caplet, capsule, granule, powder,solution, syrup, elixir, emulsion, or suspension.
 14. A method formaking a pharmaceutical composition the method comprising mixing acompound of claim 1 and a pharmaceutically acceptable carrier.
 15. Amethod of treating a disorder ameliorated by antagonizing a glucagonreceptor, comprising administering to a subject in need thereof atherapeutically effective amount of the compound of claim 1 toantagonize a glucagon receptor and treat said disorder.
 16. The methodof claim 15, wherein the disorder ameliorated by antagonizing a glucagonreceptor is selected from the group consisting of Type I diabetes, TypeII diabetes mellitus, obesity and renal disease.
 17. A method oftreating Type I diabetes, Type II diabetes mellitus, obesity or renaldisease comprising administering to a subject in need thereof atherapeutically effective amount of the pharmaceutical composition ofclaim 10 to antagonize a glucagon receptor and treat the Type Idiabetes, Type II diabetes mellitus, obesity or renal disease.
 18. Amethod of treating a condition selected from the group consisting ofType I diabetes, Type II diabetes mellitus, obesity and renal diseasecomprising administering to a subject in need thereof a therapeuticallyeffective amount of the compound of claim 4 to antagonize a glucagonreceptor.
 19. A method of treating a subject with Type I diabetes, TypeII diabetes mellitus, obesity and renal disease comprising administeringto said subject a pharmaceutical composition of claim 10 in an amounteffective to treat the subject.
 20. A method of claim 15, wherein theadministering is from 1 to 4 times per day.